Posts Tagged pregnancy

[WEB PAGE] Antidepressant Approvals Could Herald New Era in Psychiatric Drugs

Antidepressant Approvals Could Herald New Era in Psychiatric Drugs

The FDA has given the green light to the first major new classes of antidepressant therapies in decades, opening up new avenues for therapeutic development.

Bianca Nogrady, Oct 1, 2019

 

As droughts go, the one plaguing the antidepressant drug development landscape for the past few decades has been noteworthy. Since the advent of serotonin and norepinephrine reuptake inhibitors in the 1980s and 1990s, there has been a dearth of new pharmacological therapies for mood disorders, says psychiatrist Samantha Meltzer-Brody, director of the University of North Carolina’s Perinatal Psychiatry Program. “The same medications largely that were there when I went to medical school a long time ago were still the ones we’ve been using.”

Given this state of affairs, Meltzer-Brody says she had the “most modest” of expectations a few years ago when she got involved in the first clinical trial testing a new drug, SAGE-547, for postpartum depression. Developed by Massachusetts-based Sage Therapeutics, SAGE-547 is a solution of allopregnanolone, a neuroactive metabolite of the sex hormone progesterone, which plays key roles in the female reproductive system.

Progesterone and allopregnanolone levels peak during the third trimester of pregnancy, then crash immediately after delivery. Preclinical data suggested the drop in allopregnanolone could be a trigger for postpartum depression in some women. The company-funded trial involved administering SAGE-547 to a handful of patients with postpartum depression as an intravenous infusion over 48 hours.

The response in the first patient treated with SAGE-547 was dramatic. From being withdrawn and depressed with no appetite before treatment, she began smiling, talking, eating, and interacting, Meltzer-Brody says. “After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.” Three more patients were treated, with similar results. Known by the generic name brexanolone, the drug sped through Phase 2 and Phase 3 trials before being approved by the US Food and Drug Administration (FDA) on March 19.

Now marketed by Sage Therapeutics as Zulresso, the therapy is the vanguard of a new wave of antidepressants. Although the path to market hasn’t been straightforward for all drug candidates, these treatments are known for being fast-acting and effective, and have fewer side effects than previous therapies. These improvements are reflected in the price tag: the first of these new antidepressants to reach the market—Zulresso and Janssen Pharmaceuticals’ Spravato (esketamine), approved just two weeks earlier for major depressive disorder—cost up to tens of thousands of dollars for a course of treatment.

But what really sets these new depression-treating drugs apart is the “circuit-driven” approach to their development, says Sage Therapeutics’ chief research officer Jim Doherty. A research focus on basic neuroscience has expanded understanding of how different neural circuits are involved in brain function—and how to target those circuits therapeutically. “The purpose of the brain is as a communication network,” Doherty says. Instead of thinking only in terms of candidate drug molecules and receptors, “we try to think as much as we can at that level [of the whole communication network] to understand what are going to be the circuit-level consequences of our molecules.”

A better understanding of depression

For a long time, the only treatments available for depression were two classes of antidepressants known as tricyclics and monoamine oxidase inhibitors (MAOIs), both of which were discovered in the 1950s. Three decades passed before a new class emerged—the SSRIs, with the first drug Prozac (fluoxetine) launched on the market by pharma giant Eli Lilly in 1988. (See timeline on page 65.) Still the most widely prescribed antidepressants in the world, SSRIs are thought to influence mood by increasing levels of the neurotransmitter serotonin in the brain’s synapses. But their exact mechanism of action is unknown. They’re also ineffective for many people, and even when they help, can require weeks or even months to alleviate patients’ symptoms. Researchers began to ask whether approaches to antidepressant development based on more-recent neuroscience might prove more successful.

“The exciting thing for a clinician-researcher like me is to be able to see that the field is broadening in the understanding of what’s creating depression,” says Jayashri Kulkarni, psychiatrist and director of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, who is involved in a clinical trial of esketamine funded by Janssen. “The move in the last ten years has been to look at causes of depression in terms of brain chemistry as well as brain circuitry or brain physiology, and when you do that, you actually come out with some options that are really good” as potential targets for antidepressant drugs.

Brexanolone, for example, is the product of research on how to modulate the function of the brain’s gamma-aminobutyric acid type A (GABAA) receptors, which normally interact with allopregnanolone and other neuroactive hormones. The drug began life as an epilepsy therapy, but Sage soon realized its potential for treating postpartum depression.

Esketamine, meanwhile, is one of another new class of antidepressants, based on a drug that has been in clinical use for half a century. The general anesthetic and painkiller ketamine is one of the World Health Organization’s essential medicines because of its safety and efficacy in both adults and children.  A couple of decades ago, with growing awareness of the role that the neurotransmitter glutamate and its interactions with the N-methyl-D-aspartate (NMDA) receptor play in mood disorders, researchers began to investigate whether ketamine, which blocks the NMDA receptor, might also be effective in treating depression.

After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.

 —Samantha Meltzer-Brody, University of North Caro­lina

The first clinical study of ketamine for depression, published in 2000, found significant and rapid improvement in depression symptoms in seven individuals with major depression. A second randomized, placebo-controlled, double-blind crossover study in 2006 confirmed the benefits, and showed that they could be delivered within just two hours of an intravenous infusion, based on patient questionnaires. “You don’t have a suicidal patient sitting around for weeks or months trying to see if the next medication is actually going to work,” says psychiatrist and neuroscientist Ronald Duman, director of the Abraham Ribicoff Research Facilities at Yale University School of Medicine who researches ketamine but wasn’t involved in the 2006 study.

Since that research was published, interest has surged in developing new ketamine-based therapies for depression, and esketamine is the first ketamine-derived product on the market. It’s the s-enantiomer of ketamine—one of two mirror-image molecules that together make up ketamine—and is administered in a nasal spray formulation. The drug was approved by the FDA last March as an add-on therapy for treatment-resistant major depression, but not without some controversy. “The FDA gave Janssen quite a bit of flexibility,” says Todd Gould, a neuropharmacologist at the University of Maryland School of Medicine. “They only met their primary outcome in one of three acute studies.”

A typical course of esketamine involves four weeks of twice-weekly treatments, followed by maintenance doses once every one or two weeks in patients who respond, continuing for up to nine months based on clinical judgement. The choice of nasal delivery was deliberate, says Ella Daly, therapeutic area lead for mood in US Scientific Affairs at Janssen. “Unlike the intravenous formulation, the intranasal route is noninvasive, [and] we felt it would facilitate outpatient access and administration,” Daly says.

However, because esketamine, like ketamine, can have cognitive, dissociative, and even psychedelic side effects, the nasal spray must be administered in a supervised medical setting, and the patient has to remain at the clinic for at least two hours after administration. “Generally [side effects attenuate], though, with repeated dosing, so we see that reducing and being less significant,” Daly says.

Neither esketamine nor brexanolone are cheap. The list price for Spravato is $590–$885 per treatment session, or up to more than $30,000 for a full nine months of treatment at maximum dosage, while a one-time, 60-hour intravenous  infusion of Zulresso costs around $34,000. But their success has caught the attention of the pharmaceutical industry, which had been moving away from psychiatric drug development due to challenges in translating animal findings into humans, says Duman, who has received fees and grant support from Johnson & Johnson, the parent company of Janssen. “There’s a very renewed interest now because of ketamine and Spravato,” he says. “This is going to help bring big pharma back to the table.”

More new antidepressants on the horizon

Esketamine’s mirror twin, the r-enantiomer of ketamine, is also being investigated as a potential therapeutic molecule. “The preclinical data from our lab and other labs indicates that the r-ketamine is the more potent antidepressant, [but] that remains to be tested in humans,” says Gould. While the s-enantiomer is a more potent antagonist of the NMDA receptor, Gould says that doesn’t necessarily translate to stronger antidepressant effects.

Gould and others are also interested in the metabolites that result from ketamine’s breakdown in the body, after research in animals found that ketamine’s metabolites were not only necessary for its antidepressant effects but could, by themselves, induce ketamine-like responses. One of those metabolites, known as (2R,6R)-hydroxynorketamine and patented by Gould and others, is about to start Phase 1 clinical trials funded by the National Institutes of Health.

At dosages that relieve depression-like symptoms in animals, the compound “does not block the NMDA receptor, it does not produce the side effects of ketamine, and it does not appear to have the potential for addiction or abuse,” says clinical pharmacologist Carlos Zarate, chief of the section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health who, with colleagues, also has patents for ketamine and its metabolites for the treatment of mood disorders.

Zarate believes that ketamine-based drugs have great potential, especially if the abuse potential and dissociative side effects are reduced. “What we do know is that ketamine, at least in our research, seems to have more-broad therapeutic effects, called pan-therapeutic effects,” Zarate says. “It seems to work very well in anxiety,  [post-traumatic stress disorder] symptoms, anhedonia or lack of pleasure, suicidal thinking, and in fact sometimes even in people who have failed electroconvulsive therapy.”

The drug development pipeline for treatments that, like brexanolone, target the GABA receptor system may also be opening up. Sage Therapeutics is starting Phase 3 trials of another GABAA receptor modulator, called SAGE-217, for adults with major depressive disorder. A recent placebo-controlled Phase 2 study showed that the compound achieved significant improvements in depressive symptoms, without any major safety signals. “That molecule was designed to have the same pharmacology of Zulresso but to have an oral once-a-day pharmacokinetic profile,” Doherty says. The company also has other drugs in early development that target the same NMDA receptor system as ketamine.

It hasn’t all been smooth sailing. Pharmaceutical company Allergan had a high-profile failure of three Phase 3 placebo-controlled clinical trials of its NMDA receptor–targeting drug rapastinel, which did not meet the primary endpoint of preventing relapses of major depression. And both the brexanolone and esketamine Phase 3 trials detected high placebo response rates, a common feature of late-stage trials in depression that can make it difficult to demonstrate that a treatment is achieving a clinical benefit.

In the case of esketamine, one of its Phase 3 trials, carried out in patients aged 65 years and older with treatment-resistant depression, failed to show statistically significant efficacy compared to placebo. “It’s fair to say that studies in the elderly population in depression are more challenging because response rates typically are lower,” Daly says. That study also used a lower starting dose, she notes, adding that an older population may need a longer duration of treatment to show benefit.

Despite the setbacks, there is general agreement that the antidepressant landscape is undergoing a profound change for the better. “It’s going to be the new norm, in that next-generation treatments will be required to have a rapid onset of action unless they’re special or unique in some other therapeutic property,” Zarate says. “Imagine, for every episode of depression you intervene [in] very early, you could significantly reduce the amount of time our patients spend in depression, [are] not able to function, have poor quality of life, and are at risk of suicide.”

A HISTORY OF ANTIDEPRESSANTS

Researchers have been working for decades on new ways to treat depression, but the US market is still dominated by drugs that were developed in the late 1980s and early 1990s.

1952

Iproniazid, the first of the monoamine oxidase inhibitors (MAOIs), is developed, after doctors realize that isoniazid, a tuberculosis drug with a similar structure, has an unexpected euphoric effect on patients. The drug inhibits the monoamine oxidase enzyme, which interacts with several neurotransmitters in the brain, including serotonin.

1957

Imipramine, the first tricyclic antidepressant, is introduced for medical use. Derived from antihistamine compounds, this drug class blocks the reuptake of serotonin and norepinephrine into presynaptic neurons, thereby increasing extracellular levels of the neurotransmitters in the brain.

1988

Fluoxetine, better known as Prozac, makes its debut on the market as the first selective serotonin reuptake inhibitor (SSRI)—still the class of antidepressants most commonly prescribed today. By reducing the reuptake of serotonin, the drug increases the extracellular concentration of the neurotransmitter.

1989

Bupropion, a type of antidepressant that doesn’t fit into existing drug classes, is approved as a treatment for major depressive disorder. It increases dopamine and norepinephrine levels in the brain by inhibiting the neurotransmitters’ reuptake.

1993

Venlafaxine, the first of the serotonin-norepinephrine reuptake inhibitors (SNRIs), hits the market. Like the SSRIs, these drugs inhibit the reuptake of serotonin, but they additionally do the same for norepinephrine.

2013

Vortioxetine, another atypical antidepressant, is approved. In addition to inhibiting the reuptake of serotonin, vortioxetine acts as an agonist and antagonist of different serotonin receptors, with the net effect of increasing extracellular amounts of serotonin and modulating the release of other, downstream neurotransmitters.

2019

Brexanolone and esketamine, the first of a new wave of drugs born of research into the underlying brain circuitry of depression, are approved and put on the market.

via Antidepressant Approvals Could Herald New Era in Psychiatric Drugs | The Scientist Magazine®

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[ARTICLE] Principles of Epilepsy Management for Women in Their Reproductive Years – Full Text

In the United States, there are over one million women with epilepsy (WWE) in their childbearing years. Pregnancy can be challenging for this population. A number of international registries have documented that children born to these women are at increased risk for major congenital malformations (MCM), lower intelligence quotient scores and neurodevelopmental disorders, when the mother is managed on antiseizure medications (ASMs). To prevent poor neonatal outcomes for this population, safe and thoughtful management strategies are necessary. We propose to divide these management strategies into five principles. These include (I) choosing suitable ASMs for the patient’s seizure type, (II) choosing an ASM with the least teratogenic and cognitive side effects, (III) dosing at the lowest possible effective dosage, (IV) selecting the best ASM regimen as promptly as possible, even before a woman has her first menses, and (V) supplementing these patients with folic acid in order to try to enhance cognition and reduce neural tube defects.

Introduction

In the United States, there are over one million WWE in their childbearing years (1). Because of the reproductive potential of these women their management can often differ from males and post-menopausal women.

Management of seizures is traditionally guided by the classification of seizures as focal or generalized in onset. Thankfully, there are ASMs that can treat seizures in each classification. That selection is then narrowed down further in WWE based on the teratogenicity potential of these ASMs that is available from the various pregnancy registries. These registries include the North American Pregnancy Registry, The UK & Ireland Epilepsy and Pregnancy Register, EURAP Registry (includes 44 countries all around the world) and the Australian Registry.

Along with an increase of MCM some ASMs can also lead to lower intelligence quotient scores, and neurodevelopmental disorders (1). Unintended pregnancies further complicate this risk as they often lead to inadequate or delayed initiation of prenatal care and an increased risk for fetal exposure teratogenic substances such as alcohol and nicotine (2). In 2011, there were 45 unintended pregnancies for every 1,000 women aged 15–44 years (3). Similar rates are reflected worldwide in other developed countries, but are substantially higher in developing countries at 65 unintended pregnancies for every 1,000 women age 15–44 years (4). It is thus evident that WWE in their reproductive years require different management strategies to improve their healthcare outcomes as well as the health of their potential offspring.[…]

Continue —-> Frontiers | Principles of Epilepsy Management for Women in Their Reproductive Years | Neurology

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[Abstract + References] Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy – Review

Abstract

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine’s active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15–25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

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[Abstract] Do Women with epilepsy benefit from epilepsy specific pre-conception care?

Abstract

BACKGROUND

To determine how pre-conception care (PCC) influenced the outcome of epilepsy, pregnancy and malformation risk in women with epilepsy (WWE)

METHODS

All primigravida in the Kerala registry of epilepsy and pregnancy (KREP) with the final outcome of pregnancy known who were enrolled prospectively in pre-conception stage (PCC group) or first trimester of pregnancy (PRG group) were included. The two groups were compared for fetal and maternal outcomes including seizure control and complications of pregnancy.

RESULTS

There were 320 (30.4%) in PCC group and 732 in PRG group. Both groups were comparable for epilepsy classification, maternal birth defects and family history of epilepsy but the PCC group had significantly higher education (48.9%, p = .027) and employment (22.1%, p < .001). They had higher usage of folate in pre-pregnancy month (87.5%, p < .001) and first trimester (96.3%, p < .001) than PRG group. Fewer women in the PCC group were off AEDs in first trimester (5% vs 9.3%, p = .018). Within monotherapy group, use of levetiracetam (10.8%, p = .017), valproate ( 34%, p = .002) in PCC group and carbamazepine (39.1%, p = .04), phenobarbitone (13.3%, p = .001) in PRG group was significantly high. More women in this group were seizure free during pregnancy (62.8%, p = .005) than PRG group. Early fetal loss was better captured in PCC (90.6%,p = .025) than in the PRG. There was no difference in malformation rate between PCC (7.2%) and PRG groups (6.1%, p = .3).

CONCLUSION

PCC reduced the risk of seizures during pregnancy and improved the periconceptional use of folate but did not influence the fetal malformation risk.

 

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[Abstract + References] The impact of maternal epilepsy on delivery and neonatal outcomes

Abstract

Purpose

Epilepsy is a common neurological disorder that may complicate reproductive health. Our aim in this study was to provide prospective ascertainment of obstetric and neonatal outcomes in women with epilepsy and investigate whether the risk of pregnancy, delivery, and neonatal complications differed between women with epilepsy and women without epilepsy.

Methods

Pregnant women with epilepsy and women without epilepsy (control group) were prospectively evaluated during the years 2013–2018. They were regularly followed by a neurologist and obstetrician until the end of pregnancy.

Results

Delivery and perinatal outcomes were compared between 112 women diagnosed with epilepsy and 277 women without epilepsy. Epilepsy was a significant risk factor for preterm delivery, cesarean section, fetal hypoxia, and Apgar score ≤ 7 at 5 min in offspring (odds ratio (OR) = 2.83, 95% confidence interval (CI) 1.03–7.76; OR = 5.61, 95% CI 3.44–9.14; OR = 1.81, 95% CI 1.08–3.04; OR = 8.12, 95% CI 4.04–16.35, respectively). Seizures during pregnancy had influence on the preference of cesarean section as a mode of delivery (ОR = 3.39; 95% CI 1.40–8.17). The rate of perinatal hypoxia was significantly higher in children born by cesarean section (ОR = 2.84; 95% CI 1.04–7.76). There was no significant difference between women with epilepsy and controls in malformation rate.

Conclusions

Women with epilepsy had an increased risk of pregnancy and delivery complications. Cesarean section was associated with an increased risk of complications in offspring.

 

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[ARTICLE] Maternal complications in pregnancy and childbirth for women with epilepsy: Time trends in a nationwide cohort – Full Text

Abstract

Objective

Obstetric trends show changes in complication rates and maternal characteristics such as caesarean section, induced labour, and maternal age. To what degree such general time trends and changing patterns of antiepileptic drug use influence pregnancies of women with epilepsy (WWE) is unknown. Our aim was to describe changes in maternal characteristics and obstetric complications in WWE over time, and to assess changes in complication risks in WWE relative to women without epilepsy.

Methods

This was a nationwide cohort study of all first births in the Medical Birth Registry of Norway, 1999–2016. We estimated maternal characteristics, complication rates, and risks for WWE compared to women without epilepsy. Main maternal outcome measures were hypertensive disorders, bleeding in pregnancy, induction of labour, caesarean section, postpartum hemorrhage, preterm birth, small for gestational age, and epidural analgesia. Time trends were analyzed by logistic regression and comparisons made with interaction analyses.

Results

426 347 first births were analyzed, and 3077 (0.7%) women had epilepsy. In WWE there was an increase in proportions of induced labour (p<0.005) and use of epidural analgesia (p<0.005), and a reduction in mild preeclampsia (p = 0.006). However, the risk of these outcomes did not change over time. Only the risk of severe preeclampsia increased significantly over time relative to women without epilepsy (p = 0.006). In WWE, folic acid supplementation increased significantly over time (p<0.005), and there was a decrease in smoking during pregnancy (p<0.005), but these changes were less pronounced than for women without epilepsy (p<0.005).

Conclusions

During 1999–2016 there were important changes in maternal characteristics and complication rates among WWE. However, outcome risks for WWE relative to women without epilepsy did not change despite changes in antiepileptic drug use patterns. The relative risk of severe preeclampsia increased in women with epilepsy.

Introduction

Epilepsy is one of the most common chronic diseases during pregnancy.[14] Women with epilepsy (WWE) have been considered as high risk parturients with increased risk for maternal complications.[28] Almost half of women with ongoing or previous epilepsy use antiepileptic drugs (AEDs) in pregnancy to control seizures despite their potential adverse effects on the fetus and maternal complications.[2911] The pattern of antiepileptic drug use in pregnant WWE has changed markedly during the last two decades owing to newer antiepileptic drugs, primarily lamotrigine and levetiracetam, replacing older antiepileptic drugs, such as carbamazepine, phenytoin, and valproate. [1214] The newer antiepileptic drugs are better tolerated and believed to have less fetal and maternal adverse effects, but are associated with increased seizure risk during pregnancy.[10111519] Increasing maternal age, increasing maternal body mass index (BMI), and decrease in smoking during pregnancy over the last two decades should also affect WWE.[2023] These factors could be proportional or have a more complex interaction. Global trends show an increase in caesarean section rates and increased induction of labour.[2426] Such interventions are common in WWE.[24578] During the last decade, there has been an increasing focus on management of WWE during pregnancy and delivery and recent guidelines encourage close monitoring of pregnancies in WWE and strict indications for interventions.[252730] However, there is little data on how focused management and guidelines have affected maternal outcomes of WWE. A recent meta-analysis indicates a trend towards increasing rates of caesarean section and induction of labour in WWE.[31] However, different geographical populations with great variation in obstetric practice were compared to describe differences over time, and no reference populations were included. Therefore, it is not known how changes in population characteristics, obstetric practice and general complication rates have affected WWE. We expect that changes during the recent years in folate use, indications for operative interventions, and AEDs used have all influenced maternal complications in WWE during pregnancy and when giving birth.

By analyzing a stable nationwide cohort over 18 years, our aim was to describe changes in maternal characteristics and maternal complication rates in WWE over time, and to assess changes in complication risks relative to women without epilepsy. For changes in outcome risks in WWE over time, the influence of AED use and other specific factors were assessed.

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[Book Chapter] Pregnancy and Epilepsy

VD Kapadia – Medical Disorders in Pregnancy

Epilepsy is the most common neurological disorder, with 50 million people affected by it worldwide. Nearly 50% of these affected individuals are women. The burden of  epilepsy in women in India is to the tune of 2.73 million, with 52% of them being in …

Continue —> Pregnancy and Epilepsy [PDF]

 

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[NEWS] New guidance on use of valproate in women, girls of child bearing age with epilepsy published

Apr 2 2019

 

New guidance to support regulations around the use of valproate in women and girls of child bearing age with epilepsy has been published by specialists from 13 UK healthcare bodies including seven Royal Colleges.

And NICE has published a summary of updated guidance for healthcare professionals bringing together all its recommendations and other safety advice on the drug valproate.

The use of sodium valproate during pregnancy is associated with up to a 40 per cent risk of neuordevelopmental disorders and a 10 per cent risk of physical disabilities for an unborn child.

In March 2018, the Medicines and Healthcare products Regulatory Agency published guidelines which meant that valproate could no longer be prescribed for girls and women of childbearing age unless no other effective treatment was available.

Any girl or woman prescribed valproate should also be fully informed of the risks associated with the medication and the need for effective contraception.

But a year on, implementation of the guidelines have thrown up specific challenges with complex issues and individual situations where the best interests of the patient did not always appear to be met.

Claire Glazebrook, Director of Fundraising, Marketing and External Affairs at Epilepsy Society, said:

Over the last year our Helpline has received multiple calls from women, parents and healthcare professionals, all struggling to interpret the guidelines and what they mean for them as individuals. And we know that this experience is replicated across other patient organizations and clinics.

I hope this guidance will help to answer some of their questions and provide clarity in what can be a very emotional and challenging decision.

For some girls and women, they have no option but to take sodium valproate as it may be the only drug that will control their seizures. But that of course means there are some very important and potentially heartbreaking issues to consider around planning a family.

All these women and girls deserve consistency in the advice and information that they receive.”

The new pan-college guidance has been drawn up by Judy Shakespeare of the Royal College of General Practitioners and Sanjay Sisodiya of the Association of British Neurologists and Royal College of Physicians. Sanjay Sisodiya is also Director of Genomics at Epilepsy Society and Professor of Neurology at UCL.

He said: This work has come together through much valued contributions from specialists across all the national bodies involved.

“In some cases the new regulations have lead to situations where the best interests of the patients may not appear to be best served. Some of the points raised by the regulations are also complex ethical issues. We do not attempt to address all these issues in this document but hope that it will bring greater clarity for clinicians  leading to better care for women and girls with epilepsy. All women and girls have individual needs and where possible should be involved in the choices they make about their own health and plans to start a family.”

Writing in the guidance, Professor Dame Sally Davies, Chief Medical Officer for England said:

I am very pleased that the Medical Royal Colleges have come together to produce this important and helpful guidance, so that doctors and other healthcare professionals across primary and secondary care are on the same page regarding the use of sodium valproate – including around instances where its use is still appropriate.”

via New guidance on use of valproate in women, girls of child bearing age with epilepsy published

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[Abstract] Management of epilepsy in women

Journal home page for The Lancet NeurologySummary

Epilepsy is a common neurological condition in women worldwide. Hormonal changes occurring throughout a woman’s life can influence and be influenced by seizure mechanisms and antiepileptic drugs, presenting unique management challenges. Effective contraception is particularly important for women with epilepsy of childbearing potential because of antiepileptic drug-related teratogenicity and hormonal interactions; although studies reveal many women do not receive contraceptive and preconceptual counselling. Management challenges in this population include the higher risk of pregnancy complications and peripartum psychiatric problems than in women without epilepsy. Research is needed to clarify the precise role of folic acid supplementation in prevention of congenital malformations in children born to women with epilepsy. To optimise treatment of low bone density in women with epilepsy, studies investigating bone densitometryfrequency and calcium and vitamin D supplements are required. Understanding of the mechanisms linking seizures and the menopause will help to develop effective therapeutic strategies, and advances in managing epilepsy could improve quality of life for women with this condition.

 

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[BLOG POST] Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children

Bromley RL, Weston J, Marson AG.

JAMA 2017; 318:1700-1701.

Abstract

CLINICAL QUESTION:

Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children?

BOTTOM LINE:

Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).

Also see

Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224.

Both references are cited in the neurochecklist:

Antiepileptic drugs (AEDs): teratogenicity

Abstract link 1

Abstract link 2

Drugs firms ‘creating ills for every pill’. Publik15 on Flickr. https://www.flickr.com/photos/publik15/3415531899

via Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

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