Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis.

AIMS: The objective of this meta-analysis was to determine whether gestational use of hydroxychloroquine (HCQ) for autoimmune disorders leads to an increase in the risk for adverse pregnancy outcomes. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases were searched from inception to November 21 2014. Studies which reported the outcomes of pregnant women after exposure to HCQ during pregnancy and including a control (unexposed) group were included. Two independent reviewers carried out the review and the quality assessment using the Methodological Index for Non-Randomized Studies (MINORS). A random effects method was used to calculate the odds ratios (OR) for the outcomes. RESULTS: The meta-analysis reported no significant increases in rates of major congenital (OR 1.13, 95% confidence interval (CI) 0.59, 2.17), craniofacial (OR 0.62, 95% CI 0.13, 3.03), cardiovascular (OR 1.06, 95% CI 0.29, 3.86), genitourinary (OR 1.38, 95% CI 0.42, 4.53), nervous system malformations (OR 1.81, 95% CI 0.31, 10.52), stillbirth (OR 0.69, 95% CI 0.35, 1.34), low birth weight (OR 0.69, 95% CI 0.21, 2.27) or prematurity (OR 1.75, 95% CI 0.95, 3.24). The rate of spontaneous abortions, however, was found to be significantly increased in HCQ exposed pregnancies (OR 1.85, 95% CI 1.10, 3.13). No significant heterogeneity was detected among the studies for the evaluated outcomes except prematurity. CONCLUSIONS: Prenatal exposure to HCQ for autoimmune diseases does not appear to increase the risk of adverse pregnancy outcomes except spontaneous abortion rate, which may be associated with the underlying disease activity (bias by indication) and needs further investigation.

Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis.

BACKGROUND: Migraine is a common disorder among women of childbearing age. Triptan medications are effective and commonly used to treat migraines in pregnancy. However, the reproductive safety of this group of drugs has not yet been confirmed. The aim of this study was to determine the reproductive safety of triptan medications by performing a literature review and a meta-analysis. METHODS: Available publications regarding pregnancy outcomes following prenatal exposure to triptans from 1991 to 2013 were identified and reviewed according to the inclusion criteria. A random-effects meta-analysis model was implemented to combine the available pregnancy outcome data for the exposed and comparison groups. RESULTS: One case-control study and 5 cohort studies met the inclusion criteria. The included studies provided information on duration of gestation, major congenital malformations, and spontaneous abortions of infants following prenatal triptan exposure. The 6 studies included 4208 infants of women who used sumatriptan or other triptan medications, and 1,466,994 children of women who did not use triptans during pregnancy. No significant increases in rates for major congenital malformations (MCMs), prematurity, or spontaneous abortions were found when comparing the triptan-exposed group to the migraine - no triptans control group (odds ratio [OR] = 0.84 [0.61-1.16]; OR = 0.90 [0.35-2.30]; OR = 1.27 [0.58-2.79], respectively). There were no increased rate of MCMs (OR = 1.18 [0.97-1.44]) or prematurity (OR = 1.16 (0.67-1.99) when the triptan-exposed group was compared with the healthy controls; however, there was a significant increase in the rates of spontaneous abortions (OR = 3.54 [2.24-5.59]). When the migraine no-triptan group was compared with healthy controls, a significant increase in the rates of MCMs was found (OR = 1.41 [1.11-1.80]). CONCLUSION: The use of triptans during pregnancy does not appear to increase the rates for MCMs or prematurity. The increased rates of spontaneous abortions in the triptan-exposed group and the increased rates of MCM in the migraine no-triptan group require further research.

Association Between Use of Oral Contraceptives and Folate Status: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the effect of oral contraceptive use on plasma and red blood cell (RBC) folate concentrations. METHODS: We searched Medline, EMBASE, Web of Science, and the Cochrane library for human studies published from inception to June 2013 evaluating oral contraceptive use and folate status. Case-control studies, cohort studies, and clinical trials were included. A random-effects model of outcomes was used for the meta-analysis. RESULTS: A total of 2831 women in 17 studies were included in the analysis. In those whose plasma folate concentrations were available, there was a significant folate-lowering effect of oral contraceptives observed (mean reduction 1.27 µg/L; 95% CI 1.85 to 0.69, P < 0.001). Similarly, after analyzing data from 1389 women in 12 studies whose RBC folate concentrations were available, significantly lower folate status was observed among oral contraceptive users (mean reduction 59.32 µg/L; 95% CI 58.03 to 23.04, P < 0.001). CONCLUSION: Because of the reduction in blood folate concentrations associated with the use of oral contraceptives, it is critical for women of childbearing age to continue folate supplementation during oral contraceptive use.

Objectif : Mener une analyse systématique et une méta-analyse quant à l'effet du recours à la contraception orale sur les concentrations plasmatiques et érythrocytaires en folate. Méthodes : Nous avons mené des recherches dans Medline, EMBASE, Web of Science et la Cochrane library en vue d'en tirer les études menées chez l'homme, publiées entre le début de nos travaux et juin 2013, qui ont évalué l'utilisation de contraceptifs oraux et les taux de folate. Les études cas-témoins, les études de cohorte et les essais cliniques ont été admis aux fins de notre analyse. Un modèle à effets aléatoires quant aux issues a été utilisé dans le cadre de la méta-analyse. Résultats : Au total, 2 831 femmes issues de 17 études ont été admises à l'analyse. Chez les femmes pour lesquelles les concentrations plasmatiques en folate étaient disponibles, nous avons constaté que les contraceptifs oraux exerçaient un effet considérable d'atténuation de ces concentrations (baisse moyenne, 1,27 µg/l; IC à 95 %, 1,85 - 0,69, P < 0,001). De façon semblable, après avoir analysé les données traitant de 1 389 femmes issues de 12 études pour lesquelles les concentrations érythrocytaires en folate étaient disponibles, nous avons constaté une baisse considérable de ces concentrations chez les utilisatrices de contraceptifs oraux (baisse moyenne, 59,32 µg/l; IC à 95 %, 58,03 - 23,04, P < 0,001). Conclusion : En raison de la baisse des concentrations sanguines en folate qui sont associées à l'utilisation de contraceptifs oraux, il est crucial que les femmes en âge de procréer qui ont recours à une telle contraception continuent à prendre une supplémentation en folate.

The Effectiveness of Folate-Fortified Oral Contraceptives in Maintaining Optimal Folate Levels to Protect Against Neural Tube Defects: A Systematic Review.

OBJECTIVE: To conduct a systematic review evaluating the effectiveness of a folate-fortified oral contraceptive preparation in increasing blood folate concentrations to levels providing optimal protection against neural tube defects (> 906 nmol/L). METHODS: We searched Medline, EMBASE, Web of Science, and the Cochrane Library for human studies published from inception to June 2013 that evaluated oral contraceptive use and folate status. Case-control studies, cohort studies, and clinical trials were included. Efficacy and bioequivalence data were evaluated from included studies. RESULTS: Overall, efficacy and bioequivalence data for the folate-fortified oral contraceptive show that it is at least as effective as folic acid alone in raising blood folate concentrations, and that the concomitant administration of folate with the oral contraceptive component does not affect its absorption or kinetics. CONCLUSION: A folate-fortified oral contraceptive preparation provides an option for women to maintain blood folate levels, especially those who may be planning a family after the cessation of oral contraceptive therapy.

Objectif : Mener une analyse systématique de l'efficacité d'un contraceptif oral enrichi en folate pour ce qui est d'accroître les concentrations sanguines en folate jusqu'aux niveaux offrant une protection optimale contre les anomalies du tube neural (> 906 nmol/l). Méthodes : Nous avons mené des recherches dans Medline, EMBASE, Web of Science, et la Cochrane library en vue d'en tirer les études menées chez l'homme, publiées entre le début de nos travaux et juin 2013, qui ont évalué l'utilisation de contraceptifs oraux et les taux de folate. Les études cas-témoins, les études de cohorte et les essais cliniques ont été admis aux fins de notre analyse. Les issues ont été soumises à une méta-analyse faisant appel à un modèle à effets aléatoires. Résultats : De façon globale, les données sur l'efficacité et la bioéquivalence en ce qui concerne les contraceptifs oraux enrichis en folate indiquent que ceux-ci sont au moins aussi efficaces que l'acide folique administré seul pour ce qui est d'augmenter les concentrations sanguines en folate; elles indiquent également que l'administration concomitante de folate et d'un composé contraceptif oral n'en affecte ni l'absorption ni la cinétique. Conclusion : Les contraceptifs oraux enrichis en folate offrent une option aux femmes pour le maintien de leurs taux sanguins de folate; cette option s'avère particulièrement adaptée aux femmes qui pourraient souhaiter devenir enceintes à la suite de l'abandon de la contraception orale.

Association of Data Integration Technologies With Intensive Care Clinician Performance: A Systematic Review and Meta-analysis.

Importance: Sources of data in the intensive care setting are increasing exponentially, but the benefits of displaying multiparametric, high-frequency data are unknown. Decision making may not benefit from this technology if clinicians remain cognitively overburdened by poorly designed data integration and visualization technologies (DIVTs). Objective: To systematically review and summarize the published evidence on the association of user-centered DIVTs with intensive care clinician performance. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Web of Science were searched in May 2014 and January 2018. Study Selection: Studies had 3 requirements: (1) the study tested a viable DIVT, (2) participants involved were intensive care clinicians, and (3) the study reported quantitative results associated with decision making in an intensive care setting. Data Extraction and Synthesis: Of 252 records screened, 20 studies, published from 2004 to 2016, were included. The human factors framework to assess health technologies was applied to measure study completeness, and the Quality Assessment Instrument was used to assess the quality of the studies. PRISMA guidelines were adapted to conduct the systematic review and meta-analysis. Main Outcomes and Measures: Study completeness and quality; clinician performance; physical, mental, and temporal demand; effort; frustration; time to decision; and decision accuracy. Results: Of the 20 included studies, 16 were experimental studies with 410 intensive care clinician participants and 4 were survey-based studies with 1511 respondents. Scores for study completeness ranged from 27 to 43, with a maximum score of 47, and scores for study quality ranged from 46 to 79, with a maximum score of 90. Of 20 studies, DIVTs were evaluated in clinical settings in 2 studies (10%); time to decision was measured in 14 studies (70%); and decision accuracy was measured in 11 studies (55%). Measures of cognitive workload pooled in the meta-analysis suggested that any DIVT was an improvement over paper-based data in terms of self-reported performance, mental and temporal demand, and effort. With a maximum score of 22, median (IQR) mental demand scores for electronic display were 10 (7-13), tabular display scores were 8 (6.0-11.5), and novel visualization scores were 8 (6-12), compared with 17 (14-19) for paper. The median (IQR) temporal demand scores were also lower for all electronic visualizations compared with paper, with scores of 8 (6-11) for electronic display, 7 (6-11) for tabular and bar displays, 7 (5-11) for novel visualizations, and 16 (14.3-19.0) for paper. The median (IQR) performance scores improved for all electronic visualizations compared with paper (lower score indicates better self-reported performance), with scores of 6 (3-11) for electronic displays, 6 (4-11) for tabular and bar displays, 6 (4-11) for novel visualizations, and 14 (11-16) for paper. Frustration and physical demand domains of cognitive workload did not change, and differences between electronic displays were not significant. Conclusions and Relevance: This review suggests that DIVTs are associated with increased integration and consistency of data. Much work remains to identify which visualizations effectively reduce cognitive workload to enhance decision making based on intensive care data. Standardizing human factors testing by developing a repository of open access benchmarked test protocols, using a set of outcome measures, scenarios, and data sets, may accelerate the design and selection of the most appropriate DIVT.

Hyperosmolar metabolic acidosis in burn patients exposed to glycol based topical antimicrobials-A systematic review.

BACKGROUND: The well documented susceptibility of burn patients to acquired infections via damaged skin mandates application of antimicrobial agents. These agents are dissolved in various vehicles that augment skin absorption thus allowing greater efficacy. Polyethylene glycol (PEG) and Propylene glycol (PropG) are among the most commonly used vehicles, and both have been used in numerous medications and cosmetic products over the past few decades. Rarely, burn patients treated with agents containing these glycols present with a life threatening systemic toxidrome of hyperosmolar metabolic acidosis. We present a systematic review of outcomes in burn patients treated with similar agents. METHODS: Relevant studies were identified through systematic searches conducted in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Ovid), and Web of Science (Thomson Reuters), from database inception to August 4th, 2016. All publications of clinical burn patient studies included at least one arm receiving a glycol based topical therapy. RESULTS: A total of 61 studies involving 10,282 patients and 4 different antimicrobial medications fulfilled the inclusion criteria. Nine burn patients (0.09%) were documented to present with hyperosmolar metabolic acidosis during topical silver sulfadiazine treatment. Propylene glycol isolated from their blood accounted for the high osmole gap. CONCLUSION: This first systematic review found very few cases of documented hyperosmolar metabolic acidosis, all within one study that had set to specifically explore this toxidrome. High index of suspicion with frequent osmolar gap monitoring may help identify future toxicities in a timely manner.

Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: a systematic review.

BACKGROUND: Acute appendicitis is the most common surgical emergency in children. Despite this, there is no core outcome set (COS) described for randomised controlled trials (RCTs) in children with appendicitis and hence no consensus regarding outcome selection, definition and reporting. We aimed to identify outcomes currently reported in studies of paediatric appendicitis. METHODS: Using a defined, sensitive search strategy, we identified RCTs and systematic reviews (SRs) of treatment interventions in children with appendicitis. Included studies were all in English and investigated the effect of one or more treatment interventions in children with acute appendicitis or undergoing appendicectomy for presumed acute appendicitis. Studies were reviewed and data extracted by two reviewers. Primary (if defined) and all other outcomes were recorded and assigned to the core areas 'Death', 'Pathophysiological Manifestations', 'Life Impact', 'Resource Use' and 'Adverse Events', using OMERACT Filter 2.0. RESULTS: A total of 63 studies met the inclusion criteria reporting outcomes from 51 RCTs and nine SRs. Only 25 RCTs and four SRs defined a primary outcome. A total of 115 unique and different outcomes were identified. RCTs reported a median of nine outcomes each (range 1 to 14). The most frequently reported outcomes were wound infection (43 RCTs, nine SRs), intra-peritoneal abscess (41 RCTs, seven SRs) and length of stay (35 RCTs, six SRs) yet all three were reported in just 25 RCTs and five SRs. Common outcomes had multiple different definitions or were frequently not defined. Although outcomes were reported within all core areas, just one RCT and no SR reported outcomes for all core areas. Outcomes assigned to the 'Death' and 'Life Impact' core areas were reported least frequently (in six and 15 RCTs respectively). CONCLUSIONS: There is a wide heterogeneity in the selection and definition of outcomes in paediatric appendicitis, and little overlap in outcomes used across studies. A paucity of studies report patient relevant outcomes within the 'Life Impact' core area. These factors preclude meaningful evidence synthesis, and pose challenges to designing prospective clinical trials and cohort studies. The development of a COS for paediatric appendicitis is warranted.

Disease Beyond the Arch: A Systematic Review of Middle Aortic Syndrome in Childhood.

BACKGROUND: Middle aortic syndrome (MAS) is a rare clinical entity in childhood, characterized by a severe narrowing of the distal thoracic and/or abdominal aorta, and associated with significant morbidity and mortality. MAS remains a relatively poorly defined disease. This paper systematically reviews the current knowledge on MAS with respect to etiology, clinical impact, and therapeutic options. METHODS: A systematic search of 3 databases (Embase, MEDLINE, and Cochrane Central Register of Controlled Trials) yielded 1,252 abstracts that were screened based on eligibility criteria resulting in 184 full-text articles with 630 reported cases of childhood MAS. Data extracted included patient characteristics, clinical presentation, vascular phenotype, management, and outcomes. RESULTS: Most cases of MAS are idiopathic (64%), 15% are associated with Mendelian disorders, and 17% are related to inflammatory diseases. Extra-aortic involvement including renal (70%), superior mesenteric (30%), and celiac (22%) arteries is common, especially among those with associated Mendelian disorders. Inferior mesenteric artery involvement is almost never reported. The majority of cases (72%) undergo endovascular or surgical management with residual hypertension reported in 34% of cases, requiring medication or reintervention. Clinical manifestations and extent of extra-aortic involvement are lacking. CONCLUSIONS: MAS presents with significant involvement of visceral arteries with over two thirds of cases having renal artery stenosis, and one third with superior mesenteric artery stenosis. The extent of disease is worse among those with genetic and inflammatory conditions. Further studies are needed to better understand etiology, long-term effectiveness of treatment, and to determine the optimal management of this potentially devastating condition.

Perpetuating fears: bias against the null hypothesis in fetal safety of drugs as expressed in scientific citations.

BACKGROUND: Bias against negative studies (i.e., those showing no issues with fetal safety of drugs) may cause distorted interpretation with apparently safe drugs being labeled as teratogenic, causing women to terminate pregnancy or not to treat serious medical conditions. OBJECTIVE: To investigate whether "positive" studies, claiming teratogenic effects of drugs, which were later shown to be safe, have been cited more often than "negative" studies on the same topic. METHODS: We reviewed published studies on the fetal safety of 6 drugs, which were the focus of appreciable controversy over the last 5 decades (oral contraceptives, bendectin®, benzodiazepines, paroxetine, ACE inhibitors and statins). While initial highly publicized papers claimed teratogenic effects, these were subsequently contradicted by large numbers of "negative" studies. We compared medical citation patterns of the "positive" vs. "negative" papers related to these 6 drugs.Results"Positive" papers were 70% more likely to be cited than "negative" articles (median 39 vs. 23, p=0.04). In multivariate linear regression, "positivity" of results (p=0.04), the number of years since publication (p=0.01) and journal citation impact (p<0.001) all independently predicted the total number of medical citations. CONCLUSIONS: We documented bias against the null hypothesis in medical citations of fetal drug safety. Acknowledging this source of bias is critical in trying to avert the distortion of the medical knowledge created by it.

Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis.

INTRODUCTION: Folic acid fortification and supplementation to prevent neural tube defects has led to concerns regarding increased risk of colorectal cancer. The results of existing studies have been inconclusive. The purpose was to examine the relationship between level of folate intake and the incidence of colorectal cancer. METHODS: A systematic review and meta analysis were conducted. MEDLINE, Embase, and SCOPUS were searched from inception to October 2009 with the following search terms "folic acid," "folate", "colorectal cancer," "colon neoplasms," rectal neoplasms." Observational studies in adult populations were included that defined levels of folate intake and incidence of colorectal cancer. RESULT: Out of 6427 references, 27 studies met our inclusion criteria. The summary risk estimate for case control studies comparing high versus low total folate intake was 0.85 (CI 95% 0.74-0.99) with no significant heterogeneity among studies. Similarly, for cohort studies, the resulting summary risk estimate for high versus low dietary folate intake was 0.92 (CI 95% 0.81-1.05) with no significant heterogeneity. However, defining what represents a higher intake of folic acid is difficult as there is variability in the upper limit of folic acid intake used in the studies. DISCUSSION: These results suggest that higher folate intake levels offer a reduction in one of the perceived risks associated with developing colorectal cancer. These data can serve to help reassure women planning a pregnancy to increase folic intake during the preconception period to levels sufficient to prevent neural tube defects.