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 > 0.05, I 2 < 25%) and there was no evidence of publication bias. Similar results were achieved with case-control studies (OR 1.05; 95% CI 0.90-1.23). Similarly, H1 antihistamines were not associated with more spontaneous abortions (OR 1.00; 95% CI 0.83-1.20), prematurity (OR 0.96; 95% CI 0.76-1.20), stillbirth (OR 1.23; 95% CI 0.48-3.18) or low birth weight (OR 1.20; 95% CI 0.63-2.29). 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.

Bias Against the Null Hypothesis in Retrospective Registries of Gestational Drug Exposure.

OBJECTIVE: The findings in retrospective pregnancy registries related to prenatal drug exposure (collected after pregnancy outcome is known) are commonly reported in regulatory documents and in the medical literature. However, there is little information about the accuracy of the estimates of risk from such registries. We therefore sought to compare the rates of major congenital malformations reported in retrospective and prospective registries for the same drug to quantify the potential bias of retrospective reports. METHODS: We searched for all fetal safety reports related to medications for which information from both prospective and retrospective registries was available. These were published either in the peer-reviewed literature or as pharmaceutical company documents between 1984 and 2011. RESULTS: For all drugs registries studied, estimates of major congenital malformations from retrospective registries tended to be higher than the rates in prospective registries; median estimates of risk were higher by a factor of 4.18 ± 1.23 (range 2.13-5.97). CONCLUSIONS: The present study confirms a major and consistent bias against the null hypothesis in studies of teratogenic risk using retrospective registries, and this must be considered when interpreting such data. Spontaneous reporting of outcomes after exposure to a drug is highly selective towards adverse events, which families with normal pregnancy outcomes are less likely to report.

Pregnancy Outcomes Following In Utero Exposure to Second-Generation Antipsychotics: A Systematic Review and Meta-Analysis.

Second-generation antipsychotics (SGAs) are increasingly used for a variety of mental illnesses; however, the data regarding the safety of these medications during pregnancy are inconclusive and contradictory. We examined the risk of adverse pregnancy outcomes associated with in utero exposure to SGAs by conducting a systematic review and meta-analysis. We searched the databases EMBASE and MEDLINE from January 1990 to December 2014. Eligible studies had to report pregnant women who took SGAs during pregnancy (first trimester exposure if analyzing congenital malformations), follow a healthy comparison group in a similar manner, and report data on pregnancy outcomes. There was no restriction on language, sample size, or publication date. The primary outcome analyzed was major congenital malformations, and secondary outcomes included miscarriages, stillbirths, preterm births, small or large for gestational age neonates, and differences in gestational ages and birth weights. A total of 12 studies met our inclusion criteria, totalling 1782 cases and 1,322,749 controls. The use of SGA during the first trimester of pregnancy was associated with a significant increased risk for major congenital malformations (odds ratio, 2.03; 95% confidence interval, 1.41-2.93); however, no specific pattern of malformations was found. An increased risk was also found for preterm births (odds ratio, 1.85; 95% CI, 1.20-2.86). The use of SGA during pregnancy was not found to be associated with an increased risk for secondary outcomes analyzed. The absence of a specific pattern of malformations makes it difficult to identify an explicit risk posed by SGAs, and therefore, further studies sufficiently controlling for confounding factors are needed to validate these findings.

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.

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.

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 (P<0.05). The mean PSS score (24) was in the range of "much higher than the mean" for this test and the vast majority of participants were either in the "much higher than the mean" or "slightly higher than the mean" ranges. Hair cortisol determination suggests that in Tripoli, the post-war period appears to have been more stressful than the war itself. This is consistent with the fact that during the war the civilian participants were not directly involved with warfare, nor were they targeted by the international coalition fighting Gaddafi. In contrast, the post-war period was characterized by chaos and total lack of authority, with the participants exposed to injury, lack of food and destruction. CONCLUSION: This study documents the utility of hair cortisol levels to retrospectively assess stress before, during, and after an armed conflict.

Fetal and perinatal exposure to drugs and chemicals: novel biomarkers of risk.

Pregnant women are almost always excluded from randomized controlled clinical trials, as the risks to the fetus posed by most new chemical entities or approved drugs cannot be sufficiently ruled out. Hence, a major scientific challenge in this field is to discover and validate alternative tools that will fill the knowledge gap created by the lack of participation in gold-standard randomized trials. This review focuses on novel tools that allow estimation of fetal risks after exposure to therapeutic agents, such as placental perfusion studies, biomarkers of fetal exposure, and novel epidemiological and pharmacogenetic tools, all of which have been tested successfully in recent years.

Safety assessment in pediatric studies.

It typically takes many years before an association of a drug with a rare, serious adverse reaction is established. As related to pediatric drug use, evidence is even more erratic, as most drugs are used off labels. To enhance child safety, there is an urgent need to develop robust and rapid methods to identify such associations in as timely a manner as possible. In this chapter, several novel methods, both clinically based pharmacoepidemiological approaches and laboratory-based methods, are described.

A surveillance method for the early identification of idiosyncratic adverse drug reactions.

BACKGROUND: Pemoline is a CNS stimulant that was introduced in 1975 in the US and was used to treat children with attention deficit hyperactivity disorder. Pemoline was withdrawn from the market 30 years later because of fatal hepatotoxicity associated with its use. OBJECTIVE: To create a system that will estimate the potential association between a serious adverse event and a medication early in its marketing cycle. METHOD: All case reports of acute liver failure associated with pemoline and reported to the US FDA from 1975 through 1999 were reviewed. All published articles on pemoline-induced hepatotoxicity were reviewed, and the Naranjo adverse drug reaction probability scale was applied. The incidence rate of idiopathic acute liver failure was estimated from the published literature. The data were analyzed using Fisher's Exact test and relative risks (RR) were calculated. RESULTS: As early as 1978, there was a significant signal indicating that pemoline was associated with acute liver failure, with an RR of 24.08 (95% CI 4.67, 124.10; p < 0.05). With an increased number of cases, the significance of the association had been steadily increased. CONCLUSION: This method enables researchers, clinicians, drug companies and regulators to identify uncommon adverse drug reactions, caused mostly by new medications, earlier than they currently are in the course of marketing and thus quantify serious adverse events.