Offspring whose mothers experienced early life febrile seizures display long term memory deficits

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

2018 Summary

Aims:
Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not.

Methods:
The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects.

Results:
Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase. DNMT inhibitors prevented the high expression of DNMT and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs.

Conclusions:
Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

Valproate Medicine : Chronology of Research, Regulation and Knowledge

Fetal Valproate Syndrome : The “Information Gap”, Infographic by FACSaware

Infographic showing the chronology of what happened and when.

It exposes the gaps in who received information and the lack of additional regulation.

Sources FACSaware group on Facebook.

Valproate Drug Harms : EMA Public Hearing in London

Many pregnant women are still unaware of epilepsy drug risks

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

EMA Public Hearing about Drug Valproate Use in Pregnancy

Pregnant women still unaware of epilepsy drug risks

Was there a deliberate decision not to publish Valproate’s risks ?

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

Epilepsy drug warnings DO NOT reach enough women, 2017 survey finds

Almost 70% of women surveyed about a powerful epilepsy drug have not received new safety warnings about the dangers of taking it during pregnancy

Two thirds of women who take the antiepileptic drug sodium valproate said they had not received new safety warnings about the dangers of taking it during pregnancy, a survey carried out by epilepsy charities has found. A similar survey last year found that half of women taking the drug were unaware it could harm their fetus.

The new results are to be presented at a public hearing on the safety of valproate drugs organised by the European Medicines Agency on 26 September in London. …

… continue reading Women still not being told about pregnancy risks of valproate on The BMJ doi.org/10.1136/bmj.j4426, published 22 September 2017.
Featured image credit @bmj_latest.

Better understanding of the risks of valproate medicines and pregnancy

New toolkit by The Medicines and Healthcare products Regulatory Agency (MHRA)

A toolkit to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy has been launched.

The Medicines and Healthcare products Regulatory Agency (MHRA) today welcomed the launch of a new toolkit to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy.

Valproate (Epilim, Depakote and other generic brands) is a treatment for epilepsy and bipolar disorder and is prescribed to thousands of women. It is associated with a risk of birth defects and developmental disorders in children born to women who take valproate during pregnancy.

MHRA strengthened warnings on the risks of valproate in pregnancy last year, as understanding of the extent of these risks had increased. Up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects, if valproate is taken during pregnancy. The new toolkit addresses concerns that the risks of valproate are not being adequately explained to female patients.

Developed in consultation with stakeholders including healthcare professional and patient groups, the toolkit includes a credit card sized patient card to be issued by pharmacists, booklets for healthcare professionals and for patients together with a checklist of important questions and discussion points to be kept with the patient’s file. Warnings will appear on the medicine’s packaging later this year.

The MHRA is asking GPs, pharmacists, neurologists, psychiatrists, and other relevant healthcare and mental health professionals to use the toolkit to help facilitate discussion of the risks with their patients.

Sources and more information
  • New toolkit supports better understanding of the risks of valproate and pregnancy, GOV.UK Press release, 8 February 2016.
  • Toolkit on the risks of valproate medicines in female patients, GOV.UK Guidance, 8 February 2016.

Cognitive and behavioral outcomes following fetal exposure to valproate and antiepileptic drugs

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years

image of staring-child
The NEAD study is the largest prospective investigation of cognitive and behavioral outcomes following fetal exposure to valproate, carbamazepine, lamotrigine, and phenytoin. Children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. the look.

2015 Study Abstract

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate).

In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales.

Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD.

The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.

Sources and more information

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years, Epilepsy Behav. NIHMSID: NIHMS 539674, PMCID: PMC3902100, 2014 Nov 1.

Male infertility: possible association with valproate exposure

Direct effect of VPA on spermatic structure and function?

One must be cautious in extrapolating from a case report, but these 1999 findings strongly suggest a direct effect of VPA on spermatic structure and function.

1999 Study Abstract

PURPOSE:
To describe a potential association between male infertility and valproate (VPA) exposure. VPA has been implicated in the development of polycystic ovarian disease and subsequent menstrual and infertility problems in women with epilepsy. Infertility has been well described in population-based studies of persons with epilepsy. The low marital rates for men with epilepsy have previously been thought to play a major contributing role.

METHODS:
We report a case of a 32-year-old man whose wife and he were able to bear a child before the development of his epilepsy. With VPA monotherapy, the family were unable to conceive despite 4 years of unprotected intercourse. An infertility evaluation of the man revealed a very low sperm count of < 50,000/ml, no motile sperm, < 10% viability, and 100% with abnormal structure. Follicle-stimulating hormone, luteinizing hormone, and testosterone levels were normal. RESULTS: Felbamate (FBM) was initiated and VPA discontinued for improved seizure control. Within 4 months, the couple conceived their second child. A seminal analysis revealed a sperm count of > 16 million, 50% motility, 78% viability, and 72% with abnormal structure.

CONCLUSIONS:
One must be cautious in extrapolating from a case report, but these findings strongly suggest a direct effect of VPA on spermatic structure and function.

Sources and more information
  • Male infertility: possible association with valproate exposure, Epilepsia ;40(4):520-1, NCBI PMID: 10219283, , 1999 Apr

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis

Significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy

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A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. Image via Lucie Otto-Bruc.

2015 Study Abstract

Background
Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs.

Methods
We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Review’s protocol is CRD42014007547.

Findings
Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2 837 325 pregnancies). Women with epilepsy versus those without (2 809 984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02–2·32; I2=67%), antepartum haemorrhage (1·49, 1·01–2·20; I2=37%), post-partum haemorrhage (1·29, 1·13–1·49; I2=41%), hypertensive disorders (1·37, 1·21–1·55; I2=23%), induction of labour (1·67, 1·31–2·11; I2=64%), caesarean section (1·40, 1·23–1·58; I2=66%), any preterm birth (

Interpretation
A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy.

Sources and more information

Medical Condition In Case of Emergency Card

I.C.E. cards gives first responders key information on critical health issues

Those ICEcards have a fully writable reverse allows details to be filled in on who should be contacted in the event of an accident or incident.

Medical-Condition-I.C.E
Watch @DES_Journal diaporama and health posters album on Flickr.

Sources and more information

I.C.E. Cards give first responders key information on critical health issues; such as medication use, allergies or pre-existing conditions. It is easily identifiable and instantly to hand unlike carrying your details in a mobile phone, which may be locked or difficult to operate.

On Flickr®