Long-term neurocognitive adverse effects of prenatal antiepileptic drug exposure

Most women with epilepsy use antiepileptic medication during pregnancy because of seizure-related risks to mother and fetus. Most of the children exposed prenatally to antiepileptic medication are born healthy; however, there is increased risk for major congenital malformations and also unfavorable neurocognitive long-term development of the offspring. The increased risk has been correlated mainly with prenatal exposure to polytherapy and certain antiepileptic medications. Many confounding risk factors make it difficult to correlate the prenatal exposure and neurodevelopmental problems, and data of newer antiepileptic medications are lacking. In the future, larger prospective, controlled studies with extended follow-up are required to evaluate the long-term neurocognitive effects of prenatal antiepileptic medication exposure.     

Therapeutic strategies for treating epilepsy during pregnancy

Introduction: Counseling for women with epilepsy of childbearing potential surrounding pregnancy issues is of the utmost importance and should be done when antiepileptic medications are prescribed and reviewed regularly at clinic visits. Physicians must be familiar with risks associated with antiepileptic medication, and endeavor to minimize risks to a fetus while selecting best medications for epilepsy type.

Areas covered: The authors discuss the role of folic acid, updated evidence relating to the occurrence of major congenital malformations and neurocognitive risks associated with antiepileptic medication. They also examine the rationale for monitoring drug levels, optimum delivery strategies, and evidence for the safety of breastfeeding while taking antiepileptic medication.

Expert opinion: Valproate carries the highest known teratogenic risk in pregnancy and should only be prescribed to women of child-bearing potential in a specialist setting. There is a need for the ongoing register collection of risks associated with newer AEDs which lack substantial (major) data. Choosing these newer medications can create a dilemma for physicians, particularly when seizures are not well controlled or where treatment options are limited. The authors advocate a multidisciplinary team approach to managing women with epilepsy so that pregnancies in such women can be well managed in an optimum and individualized fashion.     

SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome

The aim of this review was to assess existing information about the long-term neurocognitive development of children whose mothers took SSRIs during pregnancy and/or breastfeeding. The available literature consists of 11 studies (examining a total of 306 children) that demonstrate no impairment of infant neurodevelopment following prenatal and/or postnatal exposure to SSRIs, and two studies (examining 81 children) that suggest possible unwanted effects of fetal SSRI exposure. These unwanted effects included subtle effects on motor development and motor control. Thus, the available data are not unanimous in excluding possible long-term detrimental neurodevelopmental sequelae of intrauterine exposure to SSRIs. However, it is clear that the research suggesting a lack of adverse events on infants' neurocognitive development is much more numerous and methodologically better conducted than the studies showing possible unwanted effects. Nevertheless, all reviewed studies had procedural inadequacies, and the screening instruments used have limitations, especially in the evaluation of infants. Furthermore, it is not advisable to extend the generalisations emerging from the findings of a few trials to every infant. Some infants may experience difficulties in metabolising the drugs and/or their metabolites, so the benign outcome described for most infants may not occur. Thus, the findings emerging from the reports are inconclusive and are not able to fully clarify the repercussions of maternal SSRI treatment on infants' long-term neurocognitive development. Further large, simple and well designed, randomised, prospective studies will be required for this purpose. These should also be of adequate length and performed using reproducible neurophysiological parameters in order to firmly establish the safety of these medications.     

Brain Structural Effects of Psychopharmacological Treatment in Bipolar Disorder

Bipolar disorder is associated with subtle neuroanatomical deficits including lateral ventricular enlargement, grey matter deficits incorporating limbic system structures, and distributed white matter pathophysiology. Substantial heterogeneity has been identified by structural neuroimaging studies to date and differential psychotropic medication use is potentially a substantial contributor to this. This selective review of structural neuroimaging and diffusion tensor imaging studies considers evidence that lithium, mood stabilisers, antipsychotic medication and antidepressant medications are associated with neuroanatomical variation. Most studies are negative and suffer from methodological weaknesses in terms of directly assessing medication effects on neuroanatomy, since they commonly comprise posthoc assessments of medication associations with neuroimaging metrics in small heterogenous patient groups. However the studies which report positive findings tend to form a relatively consistent picture whereby lithium and antiepileptic mood stabiliser use is associated with increased regional grey matter volume, especially in limbic structures. These findings are further supported by the more methodologically robust studies which include large numbers of patients or repeated intra-individual scanning in longitudinal designs. Some similar findings of an apparently ameliorative effect of lithium on white matter microstructure are also emerging. There is less support for an effect of antipsychotic or antidepressant medication on brain structure in bipolar disorder, but these studies are further limited by methodological difficulties. In general the literature to date supports a normalising effect of lithium and mood stabilisers on brain structure in bipolar disorder, which is consistent with the neuroprotective characteristics of these medications identified by preclinical studies.     

Medication discrepancy rates and sources upon nursing home intake: A prospective study

BackgroundMedication discrepancies at nursing home intake increase the risk of drug-related adverse events. Measuring discrepancy incidence rates and locating the origins of discrepancies can assist in identifying information exchange deficits for high-risk medications.ObjectiveTo determine class-specific discrepancy rates, to determine discordance between medication lists, and to explore patient and system-level factors associated with medication discrepancies discovered between the first and second medication reconciliations conducted at nursing home intake.MethodsMedication discrepancy data were prospectively collected from four long-term care facilities over a 9-month period. Medication discrepancies were defined as mismatched prescribing orders between at least two medication history lists. Discrepancy locations were defined as the pairs or triads of facilities between which medication history lists were discordant. Unadjusted logistic regressions were used to identify medication classes with the highest discrepancy rates and patient factors significantly associated with any medication discrepancy.Results40.8% of newly admitted or re-admitted residents and 6.3% of medications reviewed had at least one medication discrepancy discovered during the second medication reconciliation conducted at nursing home intake. Residents prescribed fewer than 14 medications were at less risk of discrepancies. Residents with Charlson Comorbidity Index of 5, COPD, HF, anemia or HTN were at greater risk of discrepancies. Respiratory and analgesic medications were twice as likely as other medication classes to be discrepant (OR = 2.2, 95% CI 1.2–4.4; OR = 2.2, 95% CI 1.3–3.5). Most discrepancies occurred between hospital and nursing home lists (44.9%), or between the hospital, nursing home, and community pharmacy lists (39.3%)ConclusionsGiven the higher risk of discrepancies within respiratory or analgesics, transitions of care teams need to prioritize residents with respiratory conditions or pain. Although re-admitted residents’ increased discrepancy risk is likely due to poorer health status, miscommunications across the nursing home, hospital and community pharmacy require further research to clarify system failures.     

The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs

A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research.     

Aging and clinical pharmacology: implications for antidepressants

The elderly frequently have changes in pharmacokinetics, sensitivity to medications, homeostatic reserve (ability to tolerate physiological challenges), exposure to multiple medications, and adherence. All of these age-associated factors can potentially influence total exposure to medication, adverse effects, and subsequent treatment outcome. Most clinical trials are performed with healthy, younger adults. Extrapolating the results of these trials to the elderly may be inappropriate, particularly for the antidepressant treatment of depression. The authors review these age-associated differences and discuss their implications for antidepressant use in older adults.     

Long term impact of prenatal exposure to SSRIs on growth and body weight in childhood: evidence from animal and human studies

Prenatal exposure to SSRIs has the potential to alter fetal 5-HT signalling during critical periods of development: the long-term consequences of which have not been well studied. Of particular interest are the potential long-term effects of prenatal SSRI exposure on growth and body weight in later life, given the role of the serotonergic system in regulating food intake and body weight. Animal studies demonstrate that changes in 5-HT homeostasis during critical periods of fetal development can lead to sex-specific molecular and functional alterations in the serotonergic and HPA systems, leading to an increased risk of overweight in male, but not female, offspring in later life. This review highlights the evidence and the need for studies in humans to determine whether prenatal SSRI exposure is associated with alterations in child growth and body weight and the importance of delineating these effects from those of the underlying maternal illness.     

Management of seizures in Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is an epilepsy syndrome that begins in childhood (between 1 and 8 years of age), worsens during latency and persists frequently into adulthood, is refractory to antiepileptic medications, and results in cognitive decline and behavioral problems in affected individuals. Seizure types consist primarily of axial tonic, atonic, and atypical absence; nocturnal tonic seizures are the most common seizure pattern in this population, but often are not one of the initial seizure patterns. Some patients also have myoclonic seizures; this seizure pattern is less frequent than the three preceding types. Although there are some cases that are cryptogenic, most are symptomatic, arising during prenatal and perinatal periods from intrauterine infections, and vascular insults to the brain. Examples of causes of Lennox-Gastaut syndrome include migrational abnormalities of the brain, late effects of CNS infections, certain genetic disorders such as tuberous sclerosis, and inherited metabolic disorders. The difficulty early in the course of Lennox-Gastaut syndrome is distinguishing this diagnosis from severe myoclonic epilepsy of infancy (Dravet syndrome) or from myoclonic-astatic epilepsy (Doose syndrome), as the seizure patterns in these three syndromes may overlap at the onset. EEG is a helpful diagnostic tool in the diagnosis of Lennox-Gastaut syndrome, usually demonstrating high voltage, bifrontal 1.5-2.5?Hz spike and wave complexes interictally, and attenuation with paroxysmal fast activity (10-13?Hz) during the ictal phase. Treatment options for Lennox-Gastaut syndrome have been less than optimal. In recent years, several drugs have been tested and approved for the treatment of this syndrome; these include felbamate, lamotrigine, topiramate, and rufinamide. The long-term outcome does not appear to be any better with the newer antiepileptic drugs than when using earlier prescribed antiepileptic drugs or polytherapy. Treatment options other than antiepileptic drugs include a ketogenic diet, vagus nerve stimulation, and corpus callosotomy. Long-term outcome of these patients relative to seizure control and cognition is poor. Most develop moderate intellectual disability within a few years of onset of the syndrome. Many develop behavioral problems with inattention, hyperactivity, and aggression.     

Clinical review procedures for the Antiretroviral Pregnancy Registry

The Antiretroviral Pregnancy Registry (APR) is an international pregnancy exposure registry designed to monitor prenatal antiretroviral medication exposures and detect any potential increase in the risk of major birth defects. The APR process imitates that of the Metropolitan Atlanta Congenital Defects Program (MACDP) modified to account for the differences in surveillance systems. The APR case definition attempts to separate prenatal and postnatal medication exposure, includes cases with multiple conditional defects only and collects cases diagnosed at later ages. Possible temporal association between defect pathogenesis and antiretroviral medication exposure includes a way to identify cases with known etiology--such as familial genetic conditions--and those with currently ambiguous pathogenesis--like hemangiomata and club feet. The APR also accounts for confounding factors like maternal alcohol use. Some defect reports automatically generate questions back to the reporter asking for more information. The APR incorporates procedures for managing and recording some of the more inconsistently reported malformations, such as microcephaly.     

Treatment strategies after a single seizure : rationale for immediate versus deferred treatment

What is the rationale for the treatment of an epileptic seizure? More specifically, should a first seizure be treated as soon as it is diagnosed or should one defer treatment until a second seizure occurs? Several studies indicate that the risk of a second (unprovoked) seizure is <50%, but studies vary in methodology and most have reviewed outcome in children only. Also, many patients were maintained on antiepileptic drugs (AEDs) during these studies, meaning that the risk for seizure recurrence was perhaps underestimated compared with the risk if untreated. Most neurologists recommend waiting for a second seizure in order to avoid complications of medications that might prove to be unnecessary. Several large studies show that delaying treatment until a second seizure occurs does not worsen the course of epilepsy or likelihood of eventual seizure control. Seizures attributable to an acute illness ('acute symptomatic', provoked seizures) usually resolve with treatment of the underlying illness and thus long-term AEDs are often unwarranted. Nevertheless, seizures arising in certain circumstances are more likely to recur and there are special considerations for patients with strokes, tumours, infections and dementia, and also after head injury or neurosurgery. Patient preferences with regard to risk and benefit also enter into the decision on whether to initiate AED treatment after a single seizure.     

Quetiapine augmentation in lactation: a series of case reports

Treating psychiatric disorders with pharmacotherapy in the breast-feeding period presents a dilemma as such treatment carries the risk of infant exposure to medication through breast milk. However, failure to institute pharmacotherapy in postnatal women in need of such treatment exposes both mother and baby to detrimental effects of the illness. Because women presenting with psychiatric disorders during the postpartum period often have complex sets of symptoms, monotherapy may not be sufficient for symptom resolution. In this case series of 6, we examined levels of psychotropic medications secreted in breast milk and performed developmental assessments of the exposed babies with the Bayley Scales of Infant Development, Second Edition. In 3 of the 6 cases, no medication was detected in the breast milk; in all but 1 case, estimated levels of infant medication exposure were calculated to be less than 0.01 mg/kg per day for each medication. Four of the 6 babies scored as being within normal limits on the Bayley Scales of Infant Development, Second Edition, whereas 2 showed mild developmental delays. In comparison to the 4 cases of typical development, the 2 showing mild delays did not have higher estimated levels of psychotropic medication exposure through breast milk. Based on these results, in our limited sample, there appears to be low levels of infant exposure to the medications through breast milk; no association was seen between developmental outcomes and exposure through breast milk of multiple pharmacological agents. These results should be interpreted with caution, and vigilance should be exercised when advising women on combinations of medications for severe mental illness who choose to nurse.     

The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins

Neurologists have little concern about the high atherosclerotic risk among epileptics. Recent evidences mount that chronic epilepsy and prolonged use of antiepileptic drugs (AEDs) are associated with multiple risk factors that are critically implicated in pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. This review is concerned with three metabolic alterations, which are attributed as major risk factors for atherosclerosis among epileptics: altered metabolism of a) homocysteine (Hcy), b) lipids and lipoproteins, and c) uric acid. Most conventional AEDs reduce folic acid levels, thereby raising Hcy levels. Hyperhomosysteinemia is recently believed to induce endothelial dysfunction and promote atherosclerosis through complex oxidative and excitatory neurotoxic molecular mechanisms. However, Hcy itself is a convulsing substance with increased seizure recurrence and intractability to antiepileptic medications. AEDs can disturb lipid metabolism with resultant hypercholestrolemia and dyslipidemia, common recognized risks for atherosclerosis. Altered uric acid metabolism is common among epileptics. Uric acid has been implicated in endothelial cell damage and decreased endothelial nitric oxide bioavailability. In the presence of atherosclerotic milieu, uric acid interacts with other substrate toxicities and increased reactive oxygen species, accelerating atherosclerosis. The above information forms the rationale for future routine screening and correction of such metabolic alterations in epileptics. A convincing argument now develops that routine polyvitamin supplementation (folic acid, vitamin B12, vitamin B6, vitamin C, vitamin E, and beta-carotene) becomes increasingly important for women and men receiving AEDs at all ages. The atheroprotective effect of multivitamins is through their antioxidant and anti-inflammatory effects together with their lipid and Hcy lowering effects.     

Anticholinergic Exposure in a Cohort of Adults Aged 80 years and Over

Anticholinergics are frequently prescribed for older adults and can lead to adverse drug events. The novel MARANTE (Muscarinic Acetylcholinergic Receptor ANTagonist Exposure) scale measures the anticholinergic exposure by incorporating potency and dosages of each medication into its calculations. The aims were to assess prevalence and intensity of the anticholinergic exposure in a longitudinal cohort study of community‐dwelling patients aged 80 years and over (n = 503) and to study the impact on mortality and hospitalization. Chronic medication use at baseline (November 2008–September 2009) was entered and codified with the Anatomical Therapeutic Chemical classification. Time‐to‐event analysis until first hospitalization or death was performed at 18 months after inclusion, using Kaplan–Meier curves. Cox regression was performed to control for covariates. Mean age was 84 years (range 80–102), and mean number of medications was 5 (range 0–16). Prevalence of anticholinergic use was 31.8%, with 9% taking ≥2 anticholinergics (range 0–4). Main indications for anticholinergics were depression, pain and gastric dysfunction. Female gender, the level of multi‐morbidity and the number of medications were associated with anticholinergic use. Mortality and hospitalization rate were 8.9% and 31.0%, respectively. After adjustment for the level of multi‐morbidity and medication intake, multi‐variable analysis showed increased risks of mortality (HR 2.3, 95% CI: 1.07–4.78) and hospitalization (HR 1.7; 95% CI: 1.13–2.59) in those with high anticholinergic exposure. The longitudinal study among Belgian community‐dwelling oldest old demonstrated great anticholinergic exposure, which was associated with increased risk of mortality and hospitalization after 18 months.     

Understanding of medications and associations with adherence,unmet needs,and perceived control of risk factors at two years post-stroke

BackgroundIt is unclear whether survivors of stroke or transient ischemic attack (TIA) routinely receive, and understand, education about secondary prevention medications.ObjectivesTo investigate whether survivors of stroke/TIA understand explanations about their prescribed prevention medications and associations with medication adherence, control of risk factors, and unmet needs.MethodsA survey was administered among survivors of stroke/TIA (random sample N = 1500) from the Australian Stroke Clinical Registry (Victoria and Queensland, 2016). Participants reported whether they understood explanations about each prescribed medication, as well as their unmet needs, perceived control of risk factors, and 30-day medication adherence. Linked pharmacy claims data were also used to determine medication adherence in the previous two years (proportion of days covered ≥80%). Outcomes were analyzed using multivariable logistic regression or multivariable negative binomial regression for frequency of unmet needs.ResultsOverall, 630/1455 eligible survivors completed the survey at ≈2.5 years post-admission (median age 69 years; 37% female). Most participants reported using prevention medications (76% antihypertensive; 84% antithrombotic; 76% lipid-lowering) but only 66–75% reported they understood explanations about their medication (75% antihypertensive; 66% antithrombotic; 74% lipid-lowering). Participants who understood explanations about their medication more often reported 30-day adherence for antihypertensive (adjusted odds ratios [aOR]: 1.96; 95% CI: 1.20–3.19), antithrombotic (aOR: 2.03; 95% CI: 1.31–3.14) and lipid-lowering medications (aOR: 1.73; 95% CI: 1.08–2.76). Similar associations were observed for antihypertensive and antithrombotic medications when pharmacy claims data were used to infer 2-year medication adherence. Understanding explanations about medications was also associated with perceived control of risk factors (hypertension: aOR: 11.08; 95% CI: 6.04–20.34; cholesterol aOR: 8.26; 95% CI: 4.72–14.47) and up to 33% fewer unmet needs related to secondary prevention.ConclusionsExpanded efforts are needed to improve the delivery of information about prevention medications to promote medication adherence, control of risk factors, and potentially prevent unmet needs following stroke/TIA.     

Exposure to bisphenol A and the development of asthma: A systematic review of cohort studies

BackgroundThere is conflicting evidence about the association between bisphenol A (BPA) exposure and childhood asthma risk. We aimed to review the epidemiological literature on the relationship between prenatal or postnatal exposure to BPA and the risk of childhood asthma/wheeze.MethodsThe PubMed database was systematically searched, and additional studies were found by searching reference lists of relevant articles.ResultsSix studies fulfilled the eligibility criteria. Three studies found that prenatal BPA exposure is associated with an increased risk of childhood wheeze, while another study reported a reduced risk of wheeze. Regarding the postnatal BPA exposure, three studies demonstrated an increased risk of childhood asthma/wheeze.ConclusionsThe mean prenatal BPA was associated with the risk of childhood wheeze/asthma. Besides, the influence of BPA exposure during the second trimester of pregnancy on the prevalence of childhood wheeze was marked. Further studies are urgently needed to explore the underlying mechanism about adverse effect of BPA exposure on childhood wheeze/asthma.