Queries on medication use during pregnancy: characterisation of the Swiss Teratogen Information Service database.

Limited information on medication safety may result in concerns on how to treat pregnant and breast-feeding patients. The Swiss Teratogen Information Service (STIS) provides information to healthcare professionals about medications during pregnancy and breast feeding. Our objective was to describe the queries addressed to the STIS over the past two decades. The STIS maintains a database of queries on pregnancy outcomes after exposure to various substances, which may be a valuable source of information. We initially analysed the general characteristics of all queries. Thereafter, we focused on exposure to medications during singleton pregnancies and associated health-related aspects. From 2000 to 2019, 7148 queries were entered into the database. An increasing number of queries was recorded over the study period, with an average of 357 queries entered into the database per year. Most of the enquirers were physicians; more specifically, gynaecologists/obstetricians (2389/7148; 33.4%) and psychiatrists (1007/7148; 14.1%). Two thirds (4747/7148; 66.4%) of the queries addressed medication intake during pregnancy; the next most frequent queries concerned planned medication in the context of pregnancy (928/7148; 13.0%) or medication use during breast-feeding (873/7148; 12.2%). In more than 50% (3611/7148) of cases, women were treated with more than one drug; altogether, 15193 medications (taken alone or in combination) were identified. The most frequent queries concerned medicines for the nervous system (ATC group N, n = 7042), with selective serotonin reuptake inhibitors (n = 1271) in the leading position, followed by benzodiazepine derivatives (n = 1102) and other antidepressants (n = 780). The next most frequently mentioned drug classes were anti-infectives for systemic use (J, n = 1586) and drugs for the alimentary tract and metabolism (A, n = 1205). Analysis of follow-up information on cases of medication exposure during singleton pregnancies (n = 2672) revealed an offspring malformation rate of 4.2%. The organ system most often affected was the musculoskeletal system, followed by the circulatory system; congenital malformations of the nervous system and chromosomal abnormalities were also seen. The three most frequently documented congenital diagnoses were malformations of cardiac septa, the brain and major arteries. Healthcare professionals often have concerns regarding the treatment of pregnant women with medication, and require professional counselling in this area. A variety of drugs are mentioned in queries addressed to the STIS, of which psycholeptics and psychoanaleptics are the most frequent. Proper guidelines on their use during pregnancy appear particularly urgent

Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas

INTRODUCTION: The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). METHODS: This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. RESULTS: Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. CONCLUSION: In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype

Validation of a Novel Method to Assess the Clinical Quality of Information in Pregnancy-Related Pharmacovigilance Case Reports: A ConcePTION Project.

To assess the causal relationship between a medicinal product and a reported event, relevant information needs to be present. Information elements for assessing cases of exposure to medicinal products during pregnancy were predefined and used in a new tool to assess the quality of information. However, the extent in which the presence or absence of these predefined information elements is associated with the overall clinical quality of these cases, as evaluated by pharmacovigilance experts, remains uncertain. We aimed to validate a novel method to assess the clinical quality of information in real-world pregnancy pharmacovigilance case reports. The clinical quality of case reports regarding medicinal product exposure and pregnancy-related outcomes was appraised from spontaneous reports, literature, Teratology Information Services (UK and Switzerland), The Dutch Pregnancy Drug Register, the Gilenya pregnancy registry and the Enhanced PV programme of Novartis. Assessment was done by means of the novel standardised tool based on the presence and relevance of information, and by expert judgement. The novel tool was validated compared to the expert assessment as the gold standard expressed as the area under the receiver operating characteristic curves, after which the sensitivity and specificity were calculated using cross-tabulations. Inter-rater variability was determined by means of weighted Cohen's kappa. One hundred and eighty-six case reports were included. The clinical quality score as assessed by the novel method was divided into three categories with cut-off values of 45% (poor to intermediate) and 65% (intermediate to excellent). Sensitivity was 0.93 and 0.96 for poor to intermediate and intermediate to excellent, respectively. Specificity was respectively 0.52 and 0.73. Inter-rater variability was 0.65 (95% confidence interval 0.53-0.78) for the newly developed approach, and 0.40 (95% confidence interval 0.28-0.52) for the gold standard assessment. The tool described in this study using the presence and relevance of elements of information is the first designed, validated and standardised method for the assessment of the quality of information of case reports in pregnancy pharmacovigilance data. This method confers less inter-rater variability compared with a quality assessment by experts of pregnancy-related pharmacovigilance data

Impact of the COVID-19 pandemic on Swiss pregnant and breastfeeding women - a cross-sectional study covering the first pandemic wave.

Information on the impact of the COVID-19 pandemic on pregnancy and breastfeeding experiences, as well as on perinatal mental health in Switzerland is limited. In Switzerland, there are few national studies and little information. Using an anonymous online survey accessible after the first wave of the outbreak in Switzerland, we have investigated how this pandemic affected pregnant and breastfeeding women. Among women who completed the survey, 69.0% (1050/1518) indicated the first wave of the pandemic affected their personal habits, 61.0% (689/1131) were affected in their work and 40.0% (632/1573) reported impaired relations with healthcare services (different denominators correspond to the number of participants who answered the question). 36.8% (110/299) of women reported an impact of the pandemic on their current pregnancy experience or breastfeeding experience (8.2%, 46/555). Overall, 11.6% (170/1467) of participants who completed the validated screening tests for mental health symptoms (Edinburgh Postnatal Depression Scale, Generalized Anxiety Disorder 7, Perceived Stress Scale) presented a score compatible with symptoms of major depression, severe anxiety or high perceived stress, which is higher than in the pre-pandemic period according to literature. Risk factors independently associated with impaired mental health were being hospitalized, having symptoms of COVID-19, living with a person with COVID-19 symptoms, having comorbidities, having experienced reduced healthcare services, having restricted usual activities and being a housewife. Protective factors independently associated were a high level of education and living with a partner. Our findings suggest that the COVID-19 pandemic might have significantly affected the well-being and mental health of pregnant and breastfeeding women, directly in the case of exposure, and indirectly as a result of the potential modifications in their life habits and in healthcare facilities

Antiepileptika bei Frauen im gebärfähigen Alter und in der Schwangerschaft: Vergleich der Fachinformationen in Deutschland und der Schweiz mit dem aktuellen Wissensstand

Zusammenfassung: Hintergrund: Viele Heilberufler nutzen Fachinformationen als eine von verschiedenen möglichen Informationsquellen zu Risiken einer Arzneimittelanwendung bei Frauen im gebärfähigen Alter und in der Schwangerschaft. Ziel dieser Arbeit ist es, eine Übersicht über das teratogene Potenzial verschiedener Antiepileptika zu präsentieren und mit den Angaben ausgewählter Fachinformationen zu vergleichen. Methoden: Es wurde eine Literaturrecherche zum teratogenen Risiko von 19 Antiepileptika durchgeführt. Die Ergebnisse wurden mit den Angaben der Fachinformationen von 38 in der Schweiz und in Deutschland erhältlichen Fertigarzneimitteln verglichen. Ergebnisse: In allen Fachinformationen wird das teratogene Risiko anhand epidemiologischer Daten diskutiert. Eine Quantifizierung des Fehlbildungsrisikos und die Anzahl dokumentierter Schwangerschaften fehlen jedoch meistens. Angaben zur Notwendigkeit der Überwachung von Plasmaspiegeln während der Schwangerschaft mit etwaiger Dosisanpassung fehlen in fünf schweizer und zwei deutschen Fachinformationen. Diskussion: Die Angaben in den Fachinformationen der untersuchten Antiepileptika zur Anwendung bei Frauen im gebärfähigen Alter und in der Schwangerschaft sind heterogen und entsprechen überwiegend nicht dem aktuellen Kenntnisstand. Eine durch die zuständigen Behörden angestoßene Überarbeitung der Fachinformationen scheint notwendig zu sein, damit diese Dokumente für Heilberufler tatsächlich von Nutzen sein können

Vaccine Willingness and Impact of the COVID-19 Pandemic on Women's Perinatal Experiences and Practices-A Multinational, Cross-Sectional Study Covering the First Wave of the Pandemic.

The COVID-19 pandemic may be of particular concern for pregnant and breastfeeding women. We aimed to explore their beliefs about the coronavirus and COVID-19 vaccine willingness and to assess the impact of the pandemic on perinatal experiences and practices. A multinational, cross-sectional, web-based study was performed in six European countries between April and July 2020. The anonymous survey was promoted via social media. In total, 16,063 women participated (including 6661 pregnant and 9402 breastfeeding women). Most responses were collected from Belgium (44%), Norway (18%) and the Netherlands (16%), followed by Switzerland (11%), Ireland (10%) and the UK (3%). Despite differences between countries, COVID-19 vaccine hesitancy was identified among 40-50% of the respondents at the end of the first wave of the pandemic and was higher among pregnant women. Education level and employment status were associated with vaccine hesitancy. The first wave had an adverse impact on pregnancy experiences and disrupted access to health services and breastfeeding support for many women. In the future, access to health care and support should be maintained at all times. Evidence-based and tailored information on COVID-19 vaccines should also be provided to pregnant and breastfeeding women to avoid unfounded concerns about the vaccines and to support shared decision making in this population

Immunohistochemical analysis of nicotinamide phosphoribosyltransferase expression in gastric and esophageal adenocarcinoma (AEG)

Nicotinamide phosphoribosyltransferase (NAMPT) represents a major component in cellular energy metabolism, which is also crucial for cancer cells that have elevated aerobic glycolysis; moreover, targeting the NAD salvage pathway by inhibition of NAMPT was shown effective in a subgroup of gastric cancer cell lines. In order to study the expression levels of NAMPT in adenocarcinoma of the esophagogastric junction and stomach (AEG/S) we performed immunohistochemical analysis in a cohort of 296 tumor samples using tissue-microarrays (TMAs). In the present investigation, we saw a high expression of NAMPT in only a minority of our large AEG/S cohort. Although we did not find a correlation between NAMPT expression and survival, subgroup analysis showed that NAMPT expression was more frequent in older patients (>65 years, p = 0.049) and was associated with a numerical shorter survival that did not reach statistical significance within this age group. In conclusion, we did not find significance for any prognostic effect of NAMPT in our AEG/S cohort; however, the evaluation of other NAD metabolic enzymes is needed as molecular predictors of response to potential NAMPT inhibition in the treatment of patients with AEG/S

Reproductive Safety of Trazodone After Maternal Exposure in Early Pregnancy: A Comparative ENTIS Cohort Study.

Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available. This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021. The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups. This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies

Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression

The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3(+), CD4(+), or CD8(+) TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy

Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas

PURPOSE: Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS: Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS: Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4(+) T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4(+) T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION: In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4(+) cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine