Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Depression Treatment in Pregnancy: Is It Safe, or Is It Not?

Prenatal depression carries substantial risks for maternal and fetal health and increases susceptibility to postpartum depression. Untreated depression in pregnancy is correlated with adverse outcomes such as an increased risk of suicidal ideation, miscarriage and neonatal growth problems. Notwithstanding concerns about the use of antidepressants, the available treatment options emphasize the importance of specialized medical supervision during gestation. The purpose of this paper is to conduct a brief literature review on the main antidepressant drugs and their effects on pregnancy, assessing their risks and benefits. The analysis of the literature shows that it is essential that pregnancy be followed by specialized doctors and multidisciplinary teams (obstetricians, psychiatrists and psychologists) who attend to the woman's needs. Depression can now be treated safely during pregnancy by choosing drugs that have no teratogenic effects and fewer side effects for both mother and child. Comprehensive strategies involving increased awareness, early diagnosis, clear guidelines and effective treatment are essential to mitigate the impact of perinatal depression.

Consensus Panel Recommendations for the Pharmacological Management of Pregnant Women with Depressive Disorders.

INTRODUCTION: The initiative of a consensus on the topic of antidepressant and anxiolytic drug use in pregnancy is developing in an area of clinical uncertainty. Although many studies have been published in recent years, there is still a paucity of authoritative evidence-based indications useful for guiding the prescription of these drugs during pregnancy, and the data from the literature are complex and require expert judgment to draw clear conclusions. METHODS: For the elaboration of the consensus, we have involved the scientific societies of the sector, namely, the Italian Society of Toxicology, the Italian Society of Neuropsychopharmacology, the Italian Society of Psychiatry, the Italian Society of Obstetrics and Gynecology, the Italian Society of Drug Addiction and the Italian Society of Addiction Pathology. An interdisciplinary team of experts from different medical specialties (toxicologists, pharmacologists, psychiatrists, gynecologists, neonatologists) was first established to identify the needs underlying the consensus. The team, in its definitive structure, includes all the representatives of the aforementioned scientific societies; the task of the team was the evaluation of the most accredited international literature as well as using the methodology of the "Nominal Group Technique" with the help of a systematic review of the literature and with various discussion meetings, to arrive at the drafting and final approval of the document. RESULTS: The following five areas of investigation were identified: (1) The importance of management of anxiety and depressive disorders in pregnancy, identifying the risks associated with untreated maternal depression in pregnancy. (2) The assessment of the overall risk of malformations with the antidepressant and anxiolytic drugs used in pregnancy. (3) The evaluation of neonatal adaptation disorders in the offspring of pregnant antidepressant/anxiolytic-treated women. (4) The long-term outcome of infants' cognitive development or behavior after in utero exposure to antidepressant/anxiolytic medicines. (5) The evaluation of pharmacological treatment of opioid-abusing pregnant women with depressive disorders. CONCLUSIONS: Considering the state of the art, it is therefore necessary in the first instance to frame the issue of pharmacological choices in pregnant women who need treatment with antidepressant and anxiolytic drugs on the basis of data currently available in the literature. Particular attention must be paid to the evaluation of the risk/benefit ratio, understood both in terms of therapeutic benefit with respect to the potential risks of the treatment on the pregnancy and on the fetal outcome, and of the comparative risk between the treatment and the absence of treatment; in the choice prescription, the specialist needs to be aware of both the potential risks of pharmacological treatment and the equally important risks of an untreated or undertreated disorder.

Long-Acting Injectable Antipsychotic Treatment during Pregnancy: A Case Series.

INTRODUCTION: Data from the literature show that prolonged-release injectable antipsychotics (LAIs) ensure constant blood drug levels better patient compliance and offer a simpler treatment regimen for both patients and caregivers. This observational-descriptive study aims to detect the possible complications found in newborns of women with bipolar or psychotic disorders and LAI therapy during pregnancy. METHODS: This study involved women with psychotic disorders during pregnancy who contacted the Teratology Information Center of Bergamo, Italy between 2016 and 2021 to receive counseling on the possible risks of exposure to LAI therapy. The follow-up procedure was carried out by telephone interview or direct contact with the patient and/or her physician. RESULTS: In this study, LAI treatment in pregnancy was not associated with an increased risk of malformations. All but one of the children in the sample were born healthy and the mothers maintained psychopathological compensation during pregnancy. CONCLUSIONS: This study showed that, despite the small size of the sample under examination, the administration of LAIs do not compromise the normal intrauterine development of the unborn child and there were no evident major malformations.

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

PURPOSE/BACKGROUND: 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. METHODS/PROCEDURES: 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. FINDINGS/RESULTS: 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. IMPLICATIONS/CONCLUSIONS: 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.

Contrast Agents during Pregnancy: Pros and Cons When Really Needed.

Many clinical conditions require radiological diagnostic exams based on the emission of different kinds of energy and the use of contrast agents, such as computerized tomography (CT), positron emission tomography (PET), magnetic resonance (MR), ultrasound (US), and X-ray imaging. Pregnant patients who should be submitted for diagnostic examinations with contrast agents represent a group of patients with whom it is necessary to consider both maternal and fetal effects. Radiological examinations use different types of contrast media, the most used and studied are represented by iodinate contrast agents, gadolinium, fluorodeoxyglucose, gastrographin, bariumsulfate, and nanobubbles used in contrast-enhanced ultrasound (CEUS). The present paper reports the available data about each contrast agent and its effect related to the mother and fetus. This review aims to clarify the clinical practices to follow in cases where a radiodiagnostic examination with a contrast medium is indicated to be performed on a pregnant patient.

Dexrazoxane for rapid extended livedo reticularis-like skin reaction due to systemic epirubicin diffusion during transcatheter arterial chemoembolization procedure for hepatocellular carcinoma.

Skin reactions after transarterial chemoembolization (TACE) with anthracyclines are rare and mostly limited to small areas. We describe a 56-year-old male with hepatocellular carcinoma treated with epirubicin chemoembolization. Immediately the procedure, pain on the right side and an extended livedo reticularis-like skin reaction appeared. Since dexrazoxane, a topoisomerase-II catalytic-cycle inhibitor, has been shown to be effective in preventing or reducing skin necrosis and ulceration following anthracycline extravasation, the drug was administered 8 h after TACE and repeated in the following 2 days. Due to marked extrahepatic diffusion of epirubicin as evidenced by computed tomography imaging, the patient showed signs of systemic organ involvement. The critically ill patient required close follow-up and intensified treatment including blood supply and pulmonary drainage of a pleural effusion. The patient presented a significant clinical improvement of the skin lesions and resolution of organ involvement with normalization of laboratory parameters after dexrazoxane. In conclusion, adverse extended skin reactions and severe systemic effects related to anthracyclines diffusion could be properly treated with dexrazoxane infusion.

Feasibility, engagement, and preliminary clinical outcomes of a digital biodata-driven intervention for anxiety and depression.

Hypothesis: The main hypothesis is that a digital, biodata-driven, and personalized program would exhibit high user retention and engagement, followed by more effective management of their depressive and anxiety symptoms. Objective: This pilot study explores the feasibility, acceptability, engagement, and potential impact on depressive and anxiety and quality of life outcomes of the 16-week Feel Program. Additionally, it examines potential correlations between engagement and impact on mental health outcomes. Methods: This single-arm study included 48 adult participants with mild or moderate depressive or anxiety symptoms who joined the 16-week Feel Program, a remote biodata-driven mental health support program created by Feel Therapeutics. The program uses a combination of evidence-based approaches and psychophysiological data. Candidates completed an online demographics and eligibility survey before enrolment. Depressive and anxiety symptoms were measured using the Patient Health Questionnaire and Generalized Anxiety Disorder Scale, respectively. The Satisfaction with Life Scale and the Life Satisfaction Questionnaire were used to assess quality of life. User feedback surveys were employed to evaluate user experience and acceptability. Results: In total, 31 participants completed the program with an overall retention rate of 65%. Completed participants spent 60 min in the app, completed 13 Mental Health Actions, including 5 Mental Health Exercises and 4.9 emotion logs on a weekly basis. On average, 96% of the completed participants were active and 76.8% of them were engaged with the sensor during the week. Sixty five percent of participants reported very or extremely high satisfaction, while 4 out of 5 were very likely to recommend the program to someone. Additionally, 93.5% of participants presented a decrease in at least one of the depressive or anxiety symptoms, with 51.6 and 45% of participants showing clinically significant improvement, respectively. Finally, our findings suggest increased symptom improvement for participants with higher engagement throughout the program. Conclusions: The findings suggest that the Feel Program may be feasible, acceptable, and valuable for adults with mild or moderate depressive and/or anxiety symptoms. However, controlled trials with bigger sample size, inclusion of a control group, and more diverse participant profiles are required in order to provide further evidence of clinical efficacy.

Open issues in management of carbon monoxide poisoning in pregnancy: practical suggestions.

Carbon monoxide (CO) poisoning during pregnancy may cause deleterious effects to the fetus. Hyperbaric oxygen therapy (HBO) in pregnancy is proven to be safe and it is considered to be beneficial, reducing the severity of the fetal injuries. However, a number of issues are still to be discussed, among them the question of the carboxyhemoglobin (COHb) levels that trigger HBO therapy in pregnant CO poisoned patients. In this letter we report some practical suggestions for organizations wishing to develop their own protocols.

Medications prescriptions in COVID-19 pregnant and lactating women: the Bergamo Teratology Information Service experience during COVID-19 outbreak in Italy.

Objectives The severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy. Methods All Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug's safety profile and compatibility with pregnancy and lactation are reported. Results Our service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved. Conclusions Hydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded.

Evaluation of the environmental sensitivity of Aegean Sea based on radiological box modeling.

A radiological box model of the Aegean Sea has been developed simulating the dispersion and fate of radionuclides in the marine environment. The model incorporates all transfer processes within abiotic and biotic compartments in combination with appropriate site-specific information. The model was calibrated using empirical radiological data, with the simulation of 137Cs dispersion after the Chernobyl. Environmental sensitivity analysis has been carried out based on Chernobyl 137Cs fallout, in terms of doses to representative marine organisms (fish, crustacean and molluscs) and human population. Comparison of the results with doses from natural sources and sensitivity estimations for shallow marine environments has been performed in order to reveal the vulnerability of each sub-region. The main characteristics and parameters controlling the radioecological processes are also discussed.

Lacosamide-induced recurrent ventricular fibrillation: A case report.

Lacosamide, a new antiepileptic drug, acts at central nervous system level but may also affect the heart, increasing the risk of cardiac arrhythmias. Only few cases of lacosamide-induced cardiac dysrhythmia have been published. We report a case of several episodes of a life-threatening ventricular fibrillation requiring cardioversion following the first doses of lacosamide as adjunctive epilepsy treatment.

Neurotoxicity of antineoplastic drugs: Mechanisms, susceptibility, and neuroprotective strategies.

This review summarizes the adverse effects on the central and/or peripheral nervous systems that may occur in response to antineoplastic drugs. In particular, we describe the neurotoxic side effects of the most commonly used drugs, such as platinum compounds, doxorubicin, ifosfamide, 5-fluorouracil, vinca alkaloids, taxanes, methotrexate, bortezomib and thalidomide. Neurotoxicity may result from direct action of compounds on the nervous system or from metabolic alterations produced indirectly by these drugs, and either the central nervous system or the peripheral nervous system, or both, may be affected. The incidence and severity of neurotoxicity are principally related to the dose, to the duration of treatment, and to the dose intensity, though other factors, such as age, concurrent pathologies, and genetic predisposition may enhance the occurrence of side effects. To avoid or reduce the onset and severity of these neurotoxic effects, the use of neuroprotective compounds and/or strategies may be helpful, thereby enhancing the therapeutic effectiveness of antineoplastic drug.

Continuous monitoring of multiple submarine springs by means of gamma-ray spectrometry.

The measurement of radiotracers is recognized as a major tool for the investigation and characterization of submarine groundwater discharges, while the use of underwater gamma-ray spectrometry has been proved a robust solution for the qualitative and quantitative determination of radionuclides in the aquatic environment. The capability of online continuous monitoring of submarine springs by means of gamma-ray spectrometry for direct estimation of SGD velocity and discharge is presented. The quantification of SGD flux rate is based on radon progenies time-series provided by two spectrometers placed above the seabed and near the water surface respectively, coupled with water level and meteorological data. The proposed methodology has been applied for a 5-month period in a coastal karstic system where multiple submarine springs occur at Anavalos-Kiveri, Greece. The estimated flux rates derived from the measured activities revealed significant SGD temporal variations with the mean discharge of 12 m3 s-1 being compatible with previous measurements. The advantages and limitations of direct SGD estimation via underwater gamma-ray monitoring are also discussed.

Clozapine-induced anemia: A case-report
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Clozapine, an atypical antipsychotic, can cause potentially life-threating side effects such as agranulocytosis. Our case presents a picture of severe anemia without any depression of the white cells or platelet lines. A 36-year-old man with treatment-resistant schizophrenia was admitted to the Psychiatric Unit for therapy assessment. After admission, he was gradually switched to clozapine treatment, 400 mg/d. General laboratory test results were normal, with a hemoglobin (Hb) level of 15.2 g/dL. The Hb level gradually decreased to 7.1 g/dL 10 weeks after switching to clozapine, when the patient underwent blood transfusion and clozapine therapy was stopped. No evidence of bleeding was noted. The reticulocyte count was less than 60.000/µL. Other anemia causes were excluded. Bone marrow aspiration performed at 10 weeks revealed red cell hypocellularity, while myelopoietic and megakaryocytic cell lines were normal. All these findings confirmed the diagnosis of pure red cell aplasia. The Hb level gradually increased to 13.3 g/dL 4 weeks after clozapine discontinuation, and the patient was discharged with olanzapine 5 mg/d. Clozapine has been reported to cause hematological abnormalities. In our patient, the diagnosis of pure red cell aplasia was made on the basis of severe and selective anemia, reticulocytopenia, and erythroid aplasia. The pathogenesis of hematologic abnormalities due to clozapine treatment is not known. Suggested mechanisms include a direct toxic effect of clozapine, or its metabolite, on the erythroid precursor cells, or formation of a drug-antibody complex. These aspects call for further and deeper research and reports of clinical observations.

Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study.

OBJECTIVE: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin-angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. METHODS: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. RESULTS: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. CONCLUSION: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I.

Temporal investigation of radionuclides and heavy metals in a coastal mining area at Ierissos Gulf, Greece.

Vertical variations of radionuclides, trace metals, and major elements were determined in two sediment cores, which were collected in the marine environment of Ierissos Gulf near Stratoni's mining area. The enrichment factors (EFs) were also estimated and provided moderately severe to extremely severe enrichment for most trace elements and Mn, describing the anthropogenic influence in the gulf during the previous century. According to the applied dating models based on 210Pb and 137Cs, the effect in the marine sediment due to the exploitation of pyrite for the production of sulfuric acid during 1912-1920 was observed. Additionally, the decrease of mining activity during 1935-1945 due to the Second World War and the type of ore exploitation, the alteration of the exploited ores, and the construction and operation of Olympiada's floatation plant during 1950-1970 were identified. The end of tailing discharging into the marine environment during 1980-2010 was also noted.

Development and optimization of an underwater in-situ cerium bromide spectrometer for radioactivity measurements in the aquatic environment.

A new medium resolution gamma-ray spectrometer consisting of a cerium bromide (CeBr3) crystal (2˝ x 2˝), is developed and optimized for radioactivity measurements in aquatic environments. This apparatus named GeoMAREA (Gamma-ray spectrometer for in-situ Marine Environmental Applications) is designed to control and prevent radio-contaminants in aquatic environments as well as to estimate the variation of natural radionuclides in marine systems for studying oceanographic processes. The system offers activity concentrations in Bq/m3 for detected gamma-ray emitters in the energy range from 150 to 2600 keV, and can provide sequential continuous monitoring data in a stand-alone mode or it can be integrated in stationary/mobile platforms for (near) real-time applications. The photopeak efficiency values were estimated via the MCNPΧ code. Two experimental points were used to validate the theoretical estimations by deploying the system in a water tank with diluted reference sources such us Caesium-137 (137Cs) and Potassium-40 (40K). The system was subsequently deployed in the field along with a conductivity-temperature (CT) sensor, to measure 40K and radon daughters in a region where submarine groundwater discharges (Anavalos, Kiveri, Greece) are present. The experimental calibration data was utilized to provide a first estimation for the background contribution around the photopeak of 40K, attributed to the Cerium Bromide (CeBr3) intrinsic activity.