New Insights into Signal Detection of the Effects of Exposures during Pregnancy

There is inadequate information on the fetal safety of drugs during pregnancy for the majority of marketed drugs. It is challenging to examine the safety and efficacy of drugs during pregnancy due to the ethical issues of exposing unborn babies to these chemicals. It often takes many years before associations between a drug and its safety, efficacy, and toxicity in pregnancy can be established. This thesis will examine strategies in signal detection of the effects of drug exposures during pregnancy. Meta-analyses have become useful in the area of clinical teratology. Observational studies provide the main source of information in these meta-analyses. Although the quality of meta-analysis of small observational studies is challenging, it is an effective strategy, as shown in the present study, in predicting correct signals to estimate teratogenicity years before large cohort studies become available. Results of retrospective pregnancy registries are commonly reported in regulatory documentations. However, little data are available on the precision of the estimates from such registries. The present study confirms a consistent bias against the null hypothesis in a retrospective registry which needs to be considered when interpreting such data as a strategy in generating safety/risk signals of new drugs. H1 antihistamines are used for the treatment of nausea and vomiting during pregnancy as well as the symptomatic relief of allergy. Although they are felt to be safe, several studies have challenged this assumption. By using meta-analysis, the safety of antihistamines has been confirmed in this thesis with over 1.3 million exposed and control subjects. Typically, after experimental animal studies, novel therapeutic modalities are tested by randomized controlled trials. Cumulative meta-analysis is an effective strategy to detect a possible time- dependent effect and potential bias against the null hypothesis, whether antioxidant treatment decreases the rates of preeclampsia. I have shown that the initial favorable effect seen in the first studies is nullified as the sample sizes and number of studies is increased. There is a need to continue using and developing the above strategies to study the safety and efficacy of drugs to improve maternal-fetal health

C-reactive protein, Epstein-Barr virus, and cortisol trajectories in refugee and non-refugee youth: Links with stress, mental health, and cognitive function during a randomized controlled trial.

Experiencing childhood adversity has been associated with significant changes in inflammation, cell-mediated immunocompetence, and cortisol secretion. Relatively few studies have examined, longitudinally, alterations to inflammatory processes during adolescence, especially outside Western contexts; none have evaluated biomarker trajectories for at-risk youth in response to a structured behavioral intervention. We conducted a randomized controlled trial evaluating the efficacy of a humanitarian intervention targeting stress-alleviation, with 12-18 year-old Syrian refugees (n = 446) and Jordanian non-refugees (n = 371) living side-by-side in war-affected communities in Jordan. We measured C-reactive protein (CRP), Epstein-Barr virus antibodies (EBV), and hair cortisol concentration (HCC) at three timepoints (pre/post intervention and 11 month follow-up), and assessed three main outcomes (psychosocial stress, mental health, and cognitive function). Using growth mixture models, regressions, and growth curve models, we identified three distinct trajectories for CRP, two for EBV, and three for HCC, and examined their associations with age, gender, BMI, poverty, and trauma. We found associations with BMI for CRP, refugee status for EBV, and BMI and gender with HCC trajectory. In terms of health outcomes, we found associations between rising CRP levels and perceived stress (B =  -2.92, p = .007), and between HCC hypersecretion and insecurity (B = 7.21, p = .017). In terms of responses to the intervention, we observed no differential impacts by CRP or EBV trajectories, unlike HCC. These results suggest that commonly-assayed biomarkers do not associate with health outcomes and respond to targeted interventions in straightforward ways. Our study is the first to examine multiple biomarker trajectories in war-affected adolescents, in order to better evaluate the extent, timing, and malleability of the biological signatures of poverty, conflict, and forced displacement

Off-label psychopharmacologic prescribing for children: History supports close clinical monitoring

The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring

When positive studies of novel therapies are subsequently nullified: cumulative meta-analyses in preeclampsia

Purpose: The purpose of this study was to examine changes over time in the pooled effect size of randomized, double-blinded, placebo-controlled trials (RCTs) published on the protective effects of antioxidants and low dose aspirin against preeclampsia, and to identify determinants that may affect such changes. Methods: Two recently published meta-analyses of RCTs examining the effects of antioxidant treatment or low dose aspirin on the rates of preeclampsia and its adverse effects were used. Chronological, cumulative meta-analyses were conducted to investigate the possibility of a time-dependent effect. The journal’s impact factor, citation numbers of each paper, and their sample size, were correlated with the risk ratio (RR) of the study. Results: The median sample size of positive antioxidant trials (i.e., showing protective effect) was tenfold smaller (median 267) than that of the negative trials (median 2120) (P = 0.017). A similar trend was seen for low dose aspirin studies. There was a significant correlation between study size and RR for the effects of antioxidants and low dose aspirin on intrauterine growth restriction (IUGR). There was no correlation between RR and citation number, or between RR and the journal’s impact factor for the two therapeutic modalities. For both modalities, the journal’s impact factor correlated significantly with the number of citations per year. Cumulative meta-analyses revealed that during the first few years and studies, there was a seeming significant protective effect of antioxidant or aspirin against preeclampsia. For both treatment, the initial protective effects gradually disappeared and nullified by larger, later studies. Conclusions: Initial studies, often published in high impact factor journals, are cited significantly more times but do not exhibit a higher likelihood of predicting a correct long term answer. Studies with smaller sample sizes are more likely to be biased against the null hypothesis. As such, cumulative meta-analysis is an effective tool in predicting potential bias against the null hypothesis and the need for additional studies

The Risk of Adverse Pregnancy Outcome After First Trimester Exposure to H1 Antihistamines: A Systematic Review and Meta-Analysis

INTRODUCTION: H1 antihistamines are used for the treatment of nausea and vomiting during pregnancy as well as the symptomatic relief of asthma, urticaria, allergy, and the common cold. Although they are overall felt to be safe during pregnancy, recently several studies have challenged this assumption, as millions of women are exposed to them in the first trimester. METHODS: Following the guidelines of PRISMA, a systematic review was performed to retrieve all published articles involving H1-antihistamine exposure during pregnancy. Electronic databases including PubMed and EMBASE were searched for possibly relevant articles published in any language up to December 2015. RESULTS: After removing duplicate publications, and excluding animal studies and studies on drug effectiveness, 342 articles were reviewed in detail and 37 studies fulfilled the inclusion criteria for the meta-analysis. In cohort studies, the risk of major malformation in the offspring of women exposed to H1 antihistamines was not higher than that of the control population (OR 1.07; 95% CI 0.98-1.16). The Q-statistic for heterogeneity of effects was not significant (p \u3e 0.05, I CONCLUSIONS: Based on our meta-analyses, which included a large number of studies, H1 antihistamines are not associated with an increased risk of major malformation or other adverse fetal outcomes. This study provides important information to both pregnant women and their healthcare providers regarding the safety and risk of H1 antihistamine use during this sensitive time

Hair Cortisol as a Biomarker of Stress in the 2011 Libyan War

Purpose: There is a substantial body of research that utilizes saliva cortisol levels to examine wartime stress; however, there is a paucity of literature that utilizes hair cortisol levels, which allows for long-term assessment of chronic stress, to investigate the stress of war. The present study aimed to evaluate changes in hair cortisol concentrations before, during, and after the 2011 Libyan war. Methods: This study examined hair cortisol concentrations of young adult women who were living in Tripoli, Libya during the 2011 war. The participants were recruited at the campus of Tripoli University. Participants needed to have at least 24 cm of hair and to have resided in Tripoli before, during and after the 2011 Libyan war. Hair was sectioned to reflect 3 month windows of cortisol exposure corresponding to periods before, during and after the war. Hair cortisol concentrations were quantified using a modified salivary ELISA test. The women were also asked to complete the Perceived Stress Scale pertaining to the post-war period. Results: Median hair cortisol concentrations in the post-war period (226.11 ng/g; range 122.95-519.85 ng/g) were significantly higher than both the pre-war (180.07 ng/g; 47.13-937.85 ng/g) and wartime (186.65 ng/g; 62.97-771.79 ng/g) periods (