Showing papers by "Gideon Koren published in 2013"

The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis.

Abstract: OBJECTIVE Depression often remains undertreated during pregnancy and there is growing evidence that untoward perinatal outcomes can result. Our systematic review and meta-analysis was conducted to determine whether maternal depression during pregnancy is associated with adverse perinatal and infant outcomes. DATA SOURCES MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from their start dates to June 2010. Keywords utilized included depressive/mood disorder, postpartum/postnatal, pregnancy/pregnancy trimesters, prenatal or antenatal, infant/neonatal outcomes, premature delivery, gestational age, birth weight, NICU, preeclampsia, breastfeeding, and Apgar. STUDY SELECTION English language studies reporting on perinatal or child outcomes associated with maternal depression were included, 3,074 abstracts were reviewed, 735 articles retrieved, and 30 studies included. DATA EXTRACTION Two independent reviewers extracted data and assessed article quality. All studies were included in the primary analyses, and between-group differences for subanalyses are also reported. RESULTS Thirty studies were eligible for inclusion. Premature delivery and decrease in breastfeeding initiation were significantly associated with maternal depression (odds ratio [OR] = 1.37; 95% CI, 1.04 to 1.81; P = .024; and OR = 0.68; 95% CI, 0.61 to 0.76; P < .0001, respectively). While birth weight (mean difference = -19.53 g; 95% CI, -64.27 to 25.20; P = .392), low birth weight (OR = 1.21; 95% CI, 0.91 to 1.60; P = .195), neonatal intensive care unit admissions (OR = 1.43; 95% CI, 0.83 to 2.47; P = .195), and preeclampsia (OR = 1.35; 95% CI, 0.95 to 1.92; P = .089) did not show significant associations in the main analyses, some subanalyses were significant. Gestational age (mean difference = -0.19 weeks; 95% CI, -0.53 to 0.14; P = .262) and Apgar scores at 1 (mean difference = -0.05; 95% CI, -0.28 to 0.17; P = .638) and 5 minutes (mean difference = 0.01; 95% CI, -0.08 to 0.11; P = .782) did not demonstrate any significant associations with depression. For premature delivery, a convenience sample study design was associated with higher ORs (OR = 2.43; 95% CI, 1.47 to 4.01; P = .001). CONCLUSIONS Maternal depression during pregnancy is associated with increased odds for premature delivery and decreased breastfeeding initiation; however, the effects are modest. More research of higher methodological quality is needed.

Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis.

Abstract: Importance Untreated depression during pregnancy has been associated with increased morbidity and mortality for both mother and child and, as such, optimal treatment strategies are required for this population. Context There are conflicting data regarding potential risks of prenatal antidepressant treatment. Objective To determine whether prenatal antidepressant exposure is associated with risk for selected adverse pregnancy or delivery outcomes. Data Sources MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and the Cochrane Library were searched from their start dates to June 30, 2010. Study Selection English-language studies reporting outcomes associated with pharmacologic treatment during pregnancy were included. We reviewed 3074 abstracts, retrieved 735 articles, and included 23 studies in this meta-analysis. Data Extraction Study design, antidepressant exposure, adjustment for confounders, and study quality were extracted by 2 independent reviewers. Results There was no significant association between antidepressant medication exposure and spontaneous abortion (odds ratio [OR], 1.47; 95% CI, 0.99 to 2.17; P = .055). Gestational age and preterm delivery were statistically significantly associated with antidepressant exposure (mean difference [MD] [weeks], −0.45; 95% CI, −0.64 to −0.25; P Conclusions and Relevance Although statistically significant associations between antidepressant exposure and pregnancy and delivery outcomes were identified, group differences were small and scores in the exposed group were typically within the normal ranges, indicating the importance of considering clinical significance. Treatment decisions must weigh the effect of untreated maternal depression against the potential adverse effects of antidepressant exposure.

Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study

Abstract: Background Paracetamol is used extensively during pregnancy, but studies regarding the potential neurodevelopmental sequelae of foetal paracetamol exposure are lacking. Method Between 1999 and 2008 all pregnant Norwegian women were eligible for recruitment into the prospective Norwegian Mother and Child Cohort Study. The mothers were asked to report on their use of paracetamol at gestational weeks 17 and 30 and at 6 months postpartum. We used data on 48 631 children whose mothers returned the 3-year follow-up questionnaire by May 2011. Within this sample were 2919 same-sex sibling pairs who were used to adjust for familial and genetic factors. We modelled psychomotor development (communication, fine and gross motor development), externalizing and internalizing behaviour problems, and temperament (emotionality, activity, sociability and shyness) based on prenatal paracetamol exposure using generalized linear regression, adjusting for a number of factors, including febrile illness, infections and co-medication use during pregnancy. Results The sibling-control analysis revealed that children exposed to prenatal paracetamol for more than 28 days had poorer gross motor development [β 0.24, 95% confidence interval (CI) 0.12–0.51], communication (β 0.20, 95% CI 0.01–0.39), externalizing behaviour (β 0.28, 95% CI 0.15–0.42), internalizing behaviour (β 0.14, 95% CI 0.01–0.28), and higher activity levels (β 0.24, 95% CI 0.11–0.38). Children exposed prenatally to short-term use of paracetamol (1–27 days) also had poorer gross motor outcomes (β 0.10, 95% CI 0.02–0.19), but the effects were smaller than with long-term use. Ibuprofen exposure was not associated with neurodevelopmental outcomes. Conclusion Children exposed to long-term use of paracetamol during pregnancy had substantially adverse developmental outcomes at 3 years of age.

Quantifying the global rates of nausea and vomiting of pregnancy: a meta analysis

Abstract: Background Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting women worldwide. It is unclear whether its prevalence and severity NVP are variable across different nations and races. Purpose To summarize global rates of NVP as reported in the literature using meta-analysis. Methods We searched Medline, Embase and Cochrane databases for all peer-reviewed articles reporting rates of NVP and/or hyperemesis gravidarum (HG). No restrictions were imposed on publication year or language. Numbers of women, studies and NVP rates were extracted and aggregated using a random effects model. Outcomes included: overall rates (i.e., women suffering any nausea or vomiting or both) in early and in late pregnancy, rates of nausea only, symptom severity, and HG rates. Results We identified 116 studies, rejecting 37 and accepting 79, of which 59 provided data for NVP (N=93,753 in 13 countries) and 26 for HG (N= 6,155,578). All developed regions of the world were represented (2 studies from Africa, 1 India; none from Latin America). Reported NVP rates varied from 35%-91% (median 69%); the meta-analytic average rate was 69.4% (CI95%:66.5%-72.3%). Among pregnant women, 32.7% had nausea without vomiting and 23.5% overall had NVP continuing into the third trimester. NVP was rated as mild in 40%, moderate in 46% and severe in 14% of cases. The prevalence of HG was 1.1% (CI95%:0.8%-1.3%), with a range of 0.3%-3.6%. Conclusions Almost 70% of women worldwide experience NVP, but reported rates vary widely. HG, the most severe form, affects 1.1%.

Herbal medicine use in pregnancy: results of a multinational study

Abstract: The use of complementary and alternative medicines (CAM) is growing in the general population. Herbal medicines are used in all countries of the world and are included in the top CAM therapies used. A multinational study on how women treat disease and pregnancy-related health ailments was conducted between October 2011 and February 2012 in Europe, North and South America and Australia. In this study, the primary aim was to determine the prevalence of herbal medicine use in pregnancy and factors related to such use across participating countries and regions. The secondary aim was to investigate who recommended the use of herbal medication in pregnancy. There were 9,459 women from 23 countries participating in the study. Of these, 28.9% reported the use of herbal medicines in pregnancy. Most herbal medicines were used for pregnancy-related health ailments such as cold and nausea. Ginger, cranberry, valerian and raspberry were the most commonly used herbs in pregnancy. The highest reported rate of herbal use medicines was in Russia (69%). Women from Eastern Europe (51.8%) and Australia (43.8%) were twice as likely to use an herbal medicine versus other regions. Women using herbal medicines were characteristically having their first child, non-smokers, using folic acid and consuming some alcohol in pregnancy. Also, women who were currently students and women with an education other than a high school degree were more likely to use herbal medicines than other women. Although 1 out of 5 women stated that a physician had recommended the herbal use, most women used herbal medicine in pregnancy on their own initiative. In this multinational study herbal medicine use in pregnancy was high although there were distinct differences in the herbs and users of herbal medicines across regions. Most commonly the women self-medicated with herbal medicine to treat pregnancy-related health ailments. More knowledge regarding the efficacy and safety of herbal medicines in pregnancy is warranted.

Cohort Profile: The Maternal‐Infant Research on Environmental Chemicals Research Platform

Abstract: Background The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. Methods Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. Results Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. Conclusions The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

A 2013 updated systematic review & meta-analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy.

Abstract: Background Although the literature suggests that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in controlling post-operative pain in the paediatric population, physicians have been reluctant to utilise these medications after tonsillectomy due to concerns of increased bleeding rates. While many surgeons prescribe opioid analgesics postoperatively, these are associated with a number of potential adverse side-effects including nausea, vomiting, constipation, excessive sedation and respiratory compromise. Objective of review To compare bleeding rates and severity between recipients of NSAIDs versus placebo or opioid analgesics for tonsillectomy. Search strategy Two authors independently searched electronic databases including PubMed, OVID, EMBASE and Cochrane Review from inception to July 2012. The keywords used included: Adenotonsillectomy, Tonsillectomy, Analgesia, Bleeding, Perioperative and Postoperative. These were then combined in various combinations with specific NSAIDs. Evaluation method A systematic review and meta-analysis of all randomised control trials comparing bleeding rates and severity between NSAIDs versus placebo or opioids post-tonsillectomy. Results A total of 36 studies met our inclusion criteria including 1747 children and 1446 adults. When all of the studies were combined in a meta-analysis using the most severe outcome, there was no increased risk of bleeding in those using NSAIDs after tonsillectomy. Use of NSAIDs in general [1.30 (0.90–1.88)] or in children [1.06 (0.65–1.74)] was not associated with increased risk of bleeding in general, most severe bleeding, secondary haemorrhage, readmission or need of reoperation due to bleeding. Similarly, there was no increased bleeding risk for specific NSAIDs in adults. In the studies looking at paediatric subjects, the overall odds ratio of bleeding was even lower than in the general population and not significant. This result is based on 18 studies, six of which had zero outcomes in either treatment arm. Similar to the general population analysis, there was no significant difference in any of the subanalyses: bleeds treated with reoperation, readmission or bleeds in children that could be managed conservatively. There were also no significant differences in the subanalyses of individual NSAIDs. Similarly, there was no significant difference in rates of bleeding in the subanalysis of studies that gave NSAIDs multiple times, for instance, both before and after surgery. Conclusions These results suggest that NSAIDs can be considered as a safe method of analgesia among children undergoing tonsillectomy.

Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence

Abstract: Objective Depression is often not optimally treated during pregnancy, partially because of conflicting data regarding antidepressant medication risk. This meta-analysis was conducted to determine whether antenatal antidepressant exposure is associated with congenital malformations and to assess the effect of known methodological limitations. Data sources EMBASE, CINAHL, PsycINFO, and MEDLINE were searched from their start dates to June 2010. Keywords of various combinations were used, including, but not limited to depressive/mood disorder, pregnancy, antidepressant drug/agent, congenital malformation, and cardiac malformation. Study selection English language studies reporting congenital malformations associated with antidepressants were included. Of 3,074 abstracts reviewed, 735 studies were retrieved and 27 studies were included. Data extraction Two reviewers working independently assessed article quality. Data on use of any antidepressant, including fluoxetine and paroxetine specifically, were extracted. Outcomes included congenital malformations, major congenital malformations, cardiovascular defects, septal heart defects (ventral septal defects and atrial septal defects), and ventral septal defects only. Results Nineteen studies were above quality threshold and make up the primary meta-analyses. Pooled relative risks (RRs) were derived by using random-effects methods. Antidepressant exposure was not associated with congenital malformations (RR = 0.93; 95% CI, 0.85-1.02; P = .113) or major malformations (RR = 1.07; 95% CI, 0.99-1.17; P = .095). However, increased risk for cardiovascular malformations (RR = 1.36; 95% CI, 1.08-1.71; P = .008) and septal heart defects (RR = 1.40; 95% CI, 1.10-1.77; P = .005) were found; the RR for ventral septal defects was similar to septal defects, although not significant (RR = 1.54; 95% CI, 0.71-3.33; P = .274). Pooled effects were significant for paroxetine and cardiovascular malformations (RR = 1.43; 95% CI, 1.08-1.88; P = .012). These results are contrasted with those addressing methodological limitations but are typically consistent. Conclusions Overall, antidepressants do not appear to be associated with an increased risk of congenital malformations, but statistical significance was found for cardiovascular malformations. Results were robust in several sensitivity analyses. Given that the RRs are marginal, they may be the result of uncontrolled confounders. Although the RRs were statistically significant, none reached clinically significant levels.

The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis.

Abstract: Objective: Conflicting reports on potential risks of antidepressant exposure during gestation for the infant have been reported in the literature. This systematic review and meta-analysis on immediate neonatal outcomes were conducted to clarify what, if any, risks are faced by infants exposed to antidepressants in utero. Subanalyses address known methodological limitations in the field. Data Sources: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from their start dates to June 2010. Various combinations of keywords were utilized including, but not limited to, depressive/mood disorder, pregnancy/pregnancy trimesters, antidepressant drugs, and neonatal effects. Study Selection: English language and cohort and casecontrol studies reporting on a cluster of signs defined as poor neonatal adaptation syndrome (PNAS) or individual clinical signs (respiratory distress and tremors) associated with pharmacologic treatment were selected. Of 3,074 abstracts reviewed, 735 articles were retrieved and 12 were included in this analysis. Data Extraction: Two independent reviewers extracted data and assessed the quality of the articles. Results: Twelve studies were retrieved that examined PNAS or the signs of respiratory distress and tremors in the infant. There was a significant association between exposure to antidepressants during pregnancy and overall occurrence of PNAS (odds ratio [OR] = 5.07; 95% CI, 3.25‐7.90; P < .0001). Respiratory distress (OR = 2.20; 95% CI, 1.81‐2.66; P < .0001) and tremors (OR = 7.89; 95% CI, 3.33‐18.73; P < .0001) were also significantly associated with antidepressant exposure. For the respiratory outcome, studies using convenience samples had significantly higher ORs (Q1 = 5.4, P = .020). No differences were found in any other moderator analyses. Conclusions: An increased risk of PNAS exists in infants exposed to antidepressant medication during pregnancy; respiratory distress and tremors also show associations. Neonatologists need to be prepared and updated in their management, and clinicians must inform their patients of this risk.

The detection of cortisol in human sweat: implications for measurement of cortisol in hair.

Abstract: Background Hair cortisol analysis has been shown to be an effective measure of chronic stress Cortisol is assumed to incorporate into hair via serum, sebum, and sweat sources; however, the extent to which sweat contributes to hair cortisol content is unknown Methods Sweat and saliva samples were collected from 17 subjects after a period of intensive exercise and analyzed by salivary enzyme-linked immunosorbent assay (ELISA) Subsequently, an in vitro test on exposure of hair to hydrocortisone was conducted Residual hair samples were immersed in a 50-ng/mL hydrocortisone solution for periods lasting 15 minutes to 24 hours, followed by a wash or no-wash condition Hair cortisol content was determined using our modified protocol for a salivary ELISA Results Postexercise control sweat cortisol concentrations ranged from 816 to 1417 ng/mL and correlated significantly with the log-transformed time of day Sweat cortisol levels significantly correlated with salivary cortisol concentrations In vitro hair exposure to a 50-ng/mL hydrocortisone solution (mimicking sweat) for 60 minutes or more resulted in significantly increased hair cortisol concentrations Washing with isopropanol did not affect immersion-increased hair cortisol concentrations Conclusions Human sweat contains cortisol in concentrations comparable with salivary cortisol levels This study suggests that perfuse sweating after intense exercise may increase cortisol concentrations detected in hair This increase likely cannot be effectively decreased with conventional washing procedures and should be considered carefully in studies using hair cortisol as a biomarker of chronic stress

Breast milk and cognitive development—the role of confounders: a systematic review

Abstract: Objectives The association between breastfeeding and child cognitive development is conflicted by studies reporting positive and null effects. This relationship may be confounded by factors associated with breastfeeding, specifically maternal socioeconomic class and IQ. Design Systematic review of the literature. Setting and participants Any prospective or retrospective study, in any language, evaluating the association between breastfeeding and cognitive development using a validated method in healthy term infants, children or adults, was included. Primary and secondary outcome measures Extracted data included the study design, target population and sample size, breastfeeding exposure, cognitive development assessment tool used and participants’ age, summary of the results prior to, and following, adjustment for confounders, and all confounders adjusted for. Study quality was assessed as well. Results 84 studies met our inclusion criteria (34 rated as high quality, 26 moderate and 24 low quality). Critical assessment of accepted studies revealed the following associations: 21 null, 28 positive, 18 null after adjusting for confounders and 17 positive—diminished after adjusting for confounders. Directionality of effect did not correlate with study quality; however, studies showing a decreased effect after multivariate analysis were of superior quality compared with other study groupings (14/17 high quality, 82%). Further, studies that showed null or diminished effect after multivariate analysis corrected for significantly more confounders (7.7±3.4) as compared with those that found no change following adjustment (5.6±4.5, p=0.04). The majority of included studies were carried out during childhood (75%) and set in high-income countries (85.5%). Conclusions Much of the reported effect of breastfeeding on child neurodevelopment is due to confounding. It is unlikely that additional work will change the current synthesis. Future studies should attempt to rigorously control for all important confounders. Alternatively, study designs using sibling cohorts discordant for breastfeeding may yield more robust conclusions.

Characteristics of Opioid-Users Whose Death Was Related to Opioid-Toxicity: A Population-Based Study in Ontario, Canada

Abstract: BACKGROUND: The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. METHODS: This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. RESULTS: Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. SIGNIFICANCECONCLUSION: These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users. Language: en

Pregnancy outcomes following maternal exposure to second-generation antipsychotics given with other psychotropic drugs: a cohort study

Abstract: Objectives Second-generation antipsychotics (SGAs), in conjunction with other psychotropic medications, are increasingly used to treat psychiatric disorders in pregnancy. The few available studies investigating the reproductive safety of SGAs did not reach conclusive results, and none have compared monotherapy with polytherapy involving other psychotropic medications. Design Descriptive cohort study using a prospectively collected database. Setting Motherisk Program, The Hospital for Sick Children, Toronto, Canada. Participants 133 women exposed to SGAs and other psychotropic drugs and 133 matched healthy controls were assessed and analysed. Outcomes of mother–child pairs exposed to SGAs in monotherapy (N=37) were compared with those exposed to SGAs with other psychotropic medications (in polytherapy; N=96). Main outcome measures Maternal, pregnancy, delivery and neonatal outcomes. Results 72% of exposed women received SGAs in polytherapy, and 101 women took their medications throughout pregnancy. These women had significantly higher pre-pregnancy weight, experienced more associated comorbidities and instrumental deliveries, and delivered a greater proportion of large for gestational age neonates. There were no differences in maternal weight gain in pregnancy between the exposed and comparison groups and between the monotherapy-exposed and polytherapy-exposed subgroups. The exposed neonates were more likely to be born premature, were admitted more often to the neonatal intensive care unit, presented with poor neonatal adaptation signs and had higher rates of congenital malformations. All the aforementioned neonatal outcomes were found mainly in the polytherapy subgroup. Conclusions The use of SGAs in polytherapy was prevalent in the assessed cohort and was associated with adverse pregnancy outcomes for both the mother and the child. In utero exposure to SGA monotherapy appears to be associated with less risk to the fetus. Future research should focus on polytherapy in pregnancy in order to define its reproductive safety and to separate the effects of medication exposure, underlying psychopathology and associated comorbidities.

Redox modification of ryanodine receptors by mitochondria-derived reactive oxygen species contributes to aberrant Ca2+ handling in ageing rabbit hearts

Abstract: Key points • Ageing is associated with increased risk of sudden cardiac death due to malignant arrhythmias. • Shortened refractoriness of Ca2+ release due to increased activity of Ca2+ release channels (RyRs) is recognized as an important contributor to cardiac-triggered arrhythmias. However, molecular mechanisms of RyR dysfunction and its contribution to arrhythmias in ageing remain to be examined. • Using ventricular myocytes isolated from old rabbit hearts we demonstrate that age-associated increase in rate of production of reactive oxygen species (ROS) by mitochondria leads to the thiol-oxidation of RyRs, which underlies the hyperactivity of the channels and thus shortened refractoriness of Ca2+ release in cardiomyocytes from the ageing heart. Mitochondria-specific scavenging of ROS in old myocytes restored the redox status of RyRs, reducing SR Ca2+ leak and arrhythmogenic spontaneous Ca2+ waves. • We conclude that increased ROS production by mitochondria contributes to age-associated increased risk of stress-induced arrhythmia and sudden cardiac death through thiol-modifications of RyRs. Abstract Ageing is associated with a blunted response to sympathetic stimulation and an increased risk of arrhythmia and sudden cardiac death. Aberrant calcium (Ca2+) handling is an important contributor to the electrical and contractile dysfunction associated with ageing. Yet, the specific molecular mechanisms underlying abnormal Ca2+ handling in ageing heart remain poorly understood. In this study, we used ventricular myocytes isolated from young (5–9 months) and old (4–6 years) rabbit hearts to test the hypothesis that changes in Ca2+ homeostasis are caused by post-translational modification of ryanodine receptors (RyRs) by mitochondria-derived reactive oxygen species (ROS) generated in the ageing heart. Changes in parameters of Ca2+ handling were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) Ca2+ dynamics in intact and permeabilized ventricular myocytes using confocal microscopy. We also measured age-related changes in ROS production and mitochondria membrane potential using a ROS-sensitive dye and a mitochondrial voltage-sensitive fluorescent indicator, respectively. In permeablized myocytes, ageing did not change SERCA activity and spark frequency but decreased spark amplitude and SR Ca2+ load suggesting increased RyR activity. Treatment with the antioxidant dithiothreitol reduced RyR-mediated SR Ca2+ leak in permeabilized myocytes from old rabbit hearts to the level comparable to young. Moreover, myocytes from old rabbits had more depolarized mitochondria membrane potential and increased rate of ROS production. Under β-adrenergic stimulation, Ca2+ transient amplitude, SR Ca2+ load, and latency of pro-arrhythmic spontaneous Ca2+ waves (SCWs) were decreased while RyR-mediated SR Ca2+ leak was increased in cardiomyocytes from old rabbits. Additionally, with β-adrenergic stimulation, scavenging of mitochondrial ROS in myocytes from old rabbit hearts restored redox status of RyRs, which reduced SR Ca2+ leak, ablated most SCWs, and increased latency to levels comparable to young. These data indicate that an age-associated increase of ROS production by mitochondria leads to the thiol-oxidation of RyRs, which underlies the hyperactivity of RyRs and thereby shortened refractoriness of Ca2+ release in cardiomyocytes from the ageing heart. This mechanism probably plays an important role in the increased incidence of arrhythmia and sudden death in the ageing population.

Neonatal pain-related stress and NFKBIA genotype are associated with altered cortisol levels in preterm boys at school age.

Abstract: Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.

Pregnancy outcomes following gabapentin use: Results of a prospective comparative cohort study

Abstract: Objectives: Our objectives were to 1) determine whether first-trimester use of gabapentin is associated with an increased risk for major malformations; 2) examine rates of spontaneous abortions, therapeutic abortions, stillbirths, mean birth weight and gestational age at delivery; and 3) examine rates of poor neonatal adaptation syndrome following late pregnancy exposure. Methods: The study design was prospective. Women were included who initially contacted the services between 5 and 8 weeks with a comparison group of women exposed to nonteratogens, collected in a similar manner. Results: We have data on 223 pregnancy outcomes exposed to gabapentin and 223 unexposed pregnancies. The rates of major malformations were similar in both groups ( p = 0.845). There was a higher rate of preterm births ( p = 0.019) and low birth weight p = 0.033) in the gabapentin group. Among infants who were exposed to gabapentin up until delivery, 23 of 61 (38%) were admitted to either the neonatal intensive care unit or special care nursery for observation and/or treatment, vs 6 of 201 (2.9%) live births in the comparison group ( p Conclusion: Our results suggest that although this sample size is not large enough to make any definitive conclusions, and there was no comparator group treated with other antiepileptic drugs, gabapentin use in pregnancy does not appear to increase the risk for major malformations. This finding and the increased risk for low birth weight and preterm birth require further investigation.

Cancer Chemotherapy and Pregnancy

Abstract: Objective To promote careful education, administration, monitoring and restricted distribution when prescribing and dispensing chemotherapeutic and potentially teratogenic medications, as well as to develop clinical recommendations for the use of cancer chemotherapy in pregnant women and women of child-bearing age. Outcomes To ensure that women of child-bearing age receiving chemotherapy can be appropriately counselled on the risks of becoming pregnant during treatment, and to provide guidance for health care practitioners treating pregnant women with antineoplastic agents. Evidence Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2011, using appropriate controlled vocabulary (e g, antineoplastic agents, neoplasms, pregnancy) and key words (e g, cancer, neoplasms, pregnancy, chemotherapy, antineoplastic agents) Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies Studies were restricted to those with available English abstracts or text. Searches were updated on a regular basis and incorporated in the guideline to October 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. Values The quality of evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Benefits, harms, and costs This guideline highlights the need to prevent pregnancy in women who are being treated for cancer and informs health care professionals treating pregnant women with chemotherapy of the potential risks of the therapy or ameliorated treatment protocols.

Autism characteristics in children with fetal alcohol spectrum disorders

Abstract: Background: Children with fetal alcohol spectrum disorders (FASD) exhibit difficulties in many cognitive and behavioral domains and also have high comorbidity with other disorders such as attention deficit/hyperactivity disorder (ADHD) and conduct disorder as well as autism. Although the FASD profile is shown to be distinct from ADHD and conduct disorder, far less is known about the commonalities with autism. The current study used a parent-rated questionnaire containing an autism subscale to explore the autistic-like features that children with FASD exhibit. Methods: Studied were 25 children with FASD (age: M = 10.3 years) and 17 normal controls (NCs; age: M = 10.2 years). As part of a larger study, all parents/caregivers completed the Social Skills Improvement System (SSIS; Gresham & Elliot, 2008), which in addition to evaluating social skills and behavior problems globally, includes an Autism subscale. Results: Between-group comparisons showed the FASD group not only scored significantly lower in socia...

Economic burden of nausea and vomiting of pregnancy in the USA.

Abstract: Background Nausea and vomiting of pregnancy (NVP) is the most common medical condition during gestation, affecting 50%-90% of women during their first trimester, and many in the second and third trimester. NVP affects women's quality of life and exerts a large economic impact on patients, caregivers and society. Objectives To estimate the overall economic burden of illness of NVP in the USA. Methods A spreadsheet model was utilized to estimate this burden including direct and indirect costs. Costs are reported in 2012 US dollars and were estimated from the perspective of society. Cost centers included drug treatments for mild to severe NVP and hospitalizations for hyperemesis gravidarum (HG), as well as time lost from work and caregiver time. Clinical, epidemiologic, and economic data were obtained from the literature to populate the model. Rates of drug use were multiplied by unit costs and summed. Results The estimated total economic burden in 2012 in the USA was $1,778,473,782 which included $1,062,847,276 (60%) in direct costs and $715,626,506 (40%) in indirect costs. Overall, the average cost to manage one woman for NVP was $1827. Costs increased with increasing severity of NVP. The estimates were conservative, as not all applicable costs could be included. Conclusions NVP results in a significant economic impact, and hence effective therapy should be sought. Future prospective research should determine in more detail what resources are utilized in the USA to manage women with NVP.

The fetal safety of thiopurines for the treatment of inflammatory bowel disease in pregnancy

Abstract: Maintaining remission of inflammatory bowel disease (IBD) during pregnancy is critical for positive pregnancy outcomes. Conflicting data exist regarding the association between thiopurine use for IBD treatment in pregnancy and adverse pregnancy outcomes and this meta-analysis aims to clarify this association. A meta-analysis was performed of all original human studies reporting outcomes in pregnancy in patients receiving thiopurines. Nine studies satisfied the inclusion criteria and a total of 494 patients with IBD and 2,782 IBD controls were reported. When compared with healthy women, those receiving thiopurines had an increased risk for congenital malformations (RR 1.45; 95% CI 1.07-1.96; p = 0.02); however, when compared with IBD controls, there was no increased risk (RR 1.37; 95% CI 0.92-2.05; p = 0.1). These data provide support for thiopurines having a minimal risk, if any, to the fetus.

CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients

Abstract: Background: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. Methods: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. Results: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). Conclusion: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients. Original submitted 7 January 2013; Revision submitted 10 April 201. © 2013 Future Medicine Ltd.

The management of nausea and vomiting of pregnancy and hyperemesis gravidarum--a 2013 update.

Abstract: Nausea and vomiting of pregnancy (NVP) affects up to 85% of all pregnancies, yet many physicians are uncertain as to how to best treat their patients in the presence of controversial data on fetal risks. This review provides an update on the management of NVP, including pharmacological and non pharmacological approaches Due to a high rate of recurrent symptoms, it is important for women to receive early treatment to reduce the severity of symptoms with the aim of preventing hospitalization and improving quality of life.

Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy.

Abstract: This guideline is intended to provide a basis for informed decision-making regarding genetic testing to identify those individuals who will not benefit from codeine therapy, as well as those who are at an increased risk for codeine-induced toxicity This guideline addresses the following key questions: 1) Should genetic testing for CYP2D6 be performed in patients prior to the initiation of codeine therapy? 2) How should patients with an indication for codeine therapy be managed based on their genotyping results for CYP2D6?

Prevalence of nausea and vomiting of pregnancy in the usa: a meta-analysis

Abstract: Background Nausea and vomiting of pregnancy (NVP) is the most common medical condition during gestation, carrying tremendous health burden, especially for the severe form, hyperemesis gravidarum (HG) The rates of NVP in the USA have not been systematically calculated Objectives To estimate the rates of NVP and HG in the USA Methods A meta-analysis was conducted of all peer-reviewed articles from the USA that provided rates of NVP in early or late pregnancy or HG Medline, Embase and Cochrane databases were searched from inception through November 2012; reviews and articles were hand searched Rates were combined across studies using a random effects model Results Forty-eight articles were identified; 15 were rejected and 33 were included for analysis Twenty-three studies of 67,602 women provided rates of NVP which had a meta-analytic rate of 686% (CI95%:644%-728%) Three of them (N=5034) reported nausea without vomiting in 286% and two studies (N=136) produced a rate for NVP during late pregnancy of 240% HG occurred in 12% of the 21 million women in 12 studies Conclusions We have summarized rates of NVP and HG, which are similar to those found in other parts of the world Almost 70% of women suffer some form of the syndrome; 12% have the severe form, most of whom were hospitalized because of the HG Future research should address issues of cost and resource utilization

Fetal Safety of Macrolides

Abstract: Macrolide antibiotics are largely used in pregnancy for different bacterial infections Their fetal safety has been studied by several groups, yielding opposing results In particular, there have been studies claiming an association between macrolides and cardiovascular malformations Exposure in early infancy has been associated with pyloric stenosis and intussusception This has led to an avoidance in prescribing macrolides to pregnant women in several Scandinavian countries The Objectives of the present study was to investigate the fetal safety of this class of drug by linking a large administrative database of drug dispensing and pregnancy outcome in Southern Israel A computerized database of medications dispensed from 1999 to 2009 to all women registered in the Clalit health maintenance organization in southern Israel was linked with two computerized databases containing maternal and infant hospitalization records Also, medical pregnancy termination data were analyzed The following confounders were controlled for: maternal age, ethnicity, maternal pregestational diabetes, parity, and the year the mother gave birth or went through medical pregnancy termination First- and third-trimester exposures to macrolide antibiotics as a group and to individual drugs were analyzed During the study period there were 105,492 pregnancies among Clalit women that met the inclusion criteria Of these, 104,380 ended in live births or dead fetuses and 1,112 in abortion due to medical reasons In the first trimester of pregnancy, 1,033 women were exposed to macrolides There was no association between macrolides and either major malformations [odds ratio (OR), 108; 95% confidence interval (CI), 084 to 138)] or specific malformations, after accounting for maternal age, parity, ethnicity, prepregnancy diabetes, and year of exposure During the third trimester of pregnancy, 959 women were exposed to macrolides There was no association between such exposure and perinatal mortality, low birth weight, low Apgar score, or preterm delivery Similarly, no associations were demonstrated with pyloric stenosis or intussusception Use of macrolides in the first trimester of pregnancy is not associated with an increased risk of major malformations Exposure in the third trimester is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner