Defining Trimester-Specific Reference Intervals for Thyroid Hormones: Insights from a Bulgarian Monocenter Study.

Background and Objectives: Pregnancy introduces various interfering factors that, alongside individual variations, impact the assessment of thyroid function tests. This underscores the necessity of defining trimester-specific reference intervals for thyroid-stimulating hormone (TSH) levels. Differences in population characteristics, including ethnicity, socio-economic factors, iodine prophylaxis, and obesity, emphasize the need to establish trimester-specific TSH ranges for women of reproductive age in the respective region or center. The aim of the present study was to establish first- and second-trimester-specific reference intervals for TSH and free thyroxine (FT4) in a relevant pregnant population. Materials and Methods: A retrospective monocenter analysis utilized the electronic database of Ob/Gyn Hospital "Dr. Shterev", Sofia, Bulgaria. The analysis involved data from 497 pregnant and 250 non-pregnant women, all without evidence of thyroid dysfunction or a family history thereof, no indication of taking medication interfering with thyroid function, no evidence of levothyroxine treatment, and no history of sterility treatment. To establish the limits of the TSH reference range, the percentile method was applied using a bootstrapping procedure following the recommendations of the International Federation of Clinical Chemistry (IFCC). Results: Trimester-specific reference intervals for TSH and FT4 in our center were established as follows: first trimester-0.38-2.91 mU/L, FT4-12.18-19.48 pmol/L; second trimester-0.72-4.22 mIU/L and 9.64-17.39 pmol/L, respectively. We also established the normal reference range for the non-pregnant control group, which is similar to that applicable in our laboratory. Conclusions: Our results differ from the fixed limits recommended by the American Thyroid Association, European Thyroid Association, and Endocrine Society Guidelines. Following the relevant established intervals would significantly impact timely diagnosis and therapy requirements for a substantial proportion of pregnant women.

Managing polypharmacy through medication review tools - pros and cons.

Inappropriate polypharmacy is a common occurrence in elderly patients, resulting in increased adverse drug reactions, nonadherence, and increased healthcare costs. Medication review and deprescribing are the primary strategies described in the literature for dealing with problematic polypharmacy. To effectively carry out the medication review, various tools have been developed. These tools can support medication review in a variety of ways. Some tools include a list of medications requiring detailed attention, while others guide medical professionals with principles and algorithms for reviewing and prescribing medicines. A third category of tools focuses on tracking and identifying symptoms that may be due to drug-related problems.

Меtformin-associated maternal and neonatal outcomes in women with gestational diabetes - a retrospective cohort study.

OBJECTIVES: To assess the maternal and neonatal outcomes in women with GDM treated with metformin, medical nutrition therapy (MNT) or insulin. MATERIAL AND METHODS: The current retrospective cohort study includes data from 233 women diagnosed with GDM who gave birth between January 2017 and January 2019 at an obstetrics and gynecology hospital in Sofia, Bulgaria. Patients were assigned to three groups, according to the treatment approach - metformin group (n = 70), insulin group (n = 40), and MNT group (n = 123). Values of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) have been evaluated at diagnosis of GDM and the third trimester of pregnancy. A comparative analysis of pregnancy outcomes and short-term neonatal characteristics in the investigated groups has been performed. RESULTS: Women indicated for pharmacological treatment (metformin or insulin) had significantly higher BMI (p < 0.01), FPG (p < 0.001), and HbA1c levels (p < 0.001) at baseline. However, during pregnancy, patients treated with metformin showed a significantly lower BMI (p < 0.01), FPG (p < 0.01), and HbA1c (p < 0.01). Neonates born to metformin-treated mothers had lower birth weight compared to those born to women in the MNT and insulin groups (metformin vs MNT, p < 0.001; metformin vs insulin, p = 0.03). The lowest incidence of newborns with macrosomia and neonatal hypoglycemia has been observed in the metformin cohort. Not a single newborn with an Apgar score under 7 has been identified in the metformin group. CONCLUSIONS: According to the current analysis, women with GDM treated with metformin demonstrated better maternal and neonatal outcomes. No short-term complications in newborns have been associated with metformin use during pregnancy.

Placental Growth Factor and Pregnancy-Associated Plasma Protein-A as Potential Early Predictors of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and one of the main causes of adverse pregnancy outcomes. An early diagnosis of GDM is of fundamental importance in clinical practice. However, the major professional organizations recommend universal screening for GDM, using a 75 g oral glucose tolerance test at 24-28 weeks of gestation. A selective screening at an early stage of pregnancy is recommended only if there are maternal risk factors for diabetes. As a result, the GDM diagnosis is often delayed and established after the appearance of complications. The manifestation of GDM is directly related to insulin resistance, which is closely associated with endothelial dysfunction. The placenta, the placental peptides and hormones play a pivotal role in the manifestation and progression of insulin resistance during pregnancy. Recently, the placental growth factor (PlGF) and plasma-associated protein-A (PAPP-A), have been shown to significantly affect both insulin sensitivity and endothelial function. The principal function of PAPP-A appears to be the cleavage of circulating insulin-like growth factor binding protein-4 while PlGF has been shown to play a central role in the development and maturation of the placental vascular system and circulation. On one hand, these factors are widely used as early predictors (11-13 weeks of gestation) of complications during pregnancy, such as preeclampsia and fetal aneuploidies, in most countries. On the other hand, there is increasing evidence for their predictive role in the development of carbohydrate disorders, but some studies are rather controversial. Therefore, this review aims to summarize the available literature about the potential of serum levels of PlGF and PAPP-A as early predictors in the diagnosis of GDM.

Benefits of using a microencapsulated vitamin D delivery system in women with polycystic ovary syndrome.

OBJECTIVE: To compare and assess the efficacy of two vitamin D delivery systems (oil-based and microencapsulated) on 25-hydroxy-vitamin D (25(OH)D) levels, body mass index (BMI) and insulin resistance (IR) in women with established polycystic ovary syndrome (PCOS) and vitamin D deficiency. MATERIALS AND METHODS: A monocentric, retrospective study was conducted, using the data of 70 female patients, who visited the endocrinology department of the "Dr. Shterev" Hospital, Sofia, Bulgaria between May 2020 and September 2020. The patients were divided into two groups according to the type of vitamin D3 supplementation: either a microencapsulated liposomal form (n=35), or a conventional oil-based form (n=35). The following clinical measures were analysed and compared: BMI, serum levels of 25(OH)D, fasting plasma glucose levels, fasting immunoreactive insulin (IRI), homeostatic model assessment (HOMA) index, levels of antimullerian hormone (AMH) II generation, and testosterone. In all selected patients, these measurements were performed at baseline and 3 months after initiation of vitamin D supplementation. RESULTS: Significantly increased serum levels of 25(OH)D were observed in patients supplemented with the microencapsulated form of vitamin D3 in the third month from the beginning of therapy, compared with the control group (p=0.003). In the microencapsulated vitamin D group, there was a decrease in IRI serum levels (p=0.023), HOMA-IR (p=0.021), serum AMH (p=0.010) and testosterone levels (p=0.006). The fasting plasma glucose levels did not change significantly. CONCLUSION: The results of our study show that the patients supplemented with a microencapsulated form of vitamin D3 achieved faster compensation of 25(OH)D levels, which in turn, under equal conditions, led to significant improvement in the metabolic profile, in particular insulin sensitivity.

The Role of Placental Growth Factor in the Prediction of Carbohydrate and Thyroid Disorders during Pregnancy.

Background and objectives: To assess whether placental growth factor (PlGF) levels may have a predictive value for the onset of gestational diabetes mellitus (GDM) and thyroid dysfunction during pregnancy. Materials and Methods: This single-center retrospective analysis was conducted at the Specialized Hospital for Active Treatment in Obstetrics and Gynecology "Dr. Shterev", Sofia, Bulgaria, from December 2017 to December 2019. Using pregnant women's electronic records, we analyzed and compared the data of 412 women diagnosed with GDM and 250 women without evidence for carbohydrate disorders. Thyroid function was tested in all patients at the time of performing GDM screening. The following measurements were compared and assessed: body mass index (BMI), fasting blood glucose levels, thyroid-stimulating hormone levels (TSH), free thyroxine, and triiodothyronine (FT4 and FT3) levels, and serum placental growth factor (PlGF). The sensitivity and specificity of PlGF as a predictive marker for GDM and thyroid dysfunction were analyzed using receiver operating characteristic (ROC) curves. Results: There were no significant differences between GDM and control groups in terms of age and BMI (p > 0.05). In patients with established GDM, the PlGF corrected multiple of the median (MoM) was significantly higher compared to the control group (0.9 vs. 0.7, p < 0.001). The ROC-AUC for the prediction of GDM and thyroid dysfunction during pregnancy was 0.68 (95% CI 0.64-0.72) and 0.61 (95% CI 0.57-0.65), respectively. Conclusions: Our results underscore the potential role of PlGF as a biomarker in the prediction and diagnosis of GDM and thyroid dysfunction during pregnancy.

Gestational diabetes mellitus: a growing economic concern.

Gestational diabetes mellitus (GDM) is a common pregnancy complication. Recent epidemiological data have shown that GDM prevalence has been on the increase worldwide. GDM could lead to adverse pregnancy outcomes and is usually associated with higher costs for its treatment and management. Pharmacoeconomics has become a crucial component of the healthcare systems in recent years because of the steadily rising costs. Despite this, there are few pharmacoeconomic studies evaluating the expenses of pregnancies impacted by GDM.

Potential role of biochemical placentation markers - pregnancy associated plasma protein-A and human chorionic gonadotropin for early gestational diabetes screening - a pilot study.

OBJECTIVES: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. The universal screening for GDM is usually performed between 24-28 weeks' gestation. This often delays the diagnosis and could increase the risk of adverse pregnancy outcomes. Some of the biochemical placental markers - pregnancy associated plasma protein A (PAPP-A) and free-ß human chorionic gonadotropin (hCG), probably could provide a diagnostic value for GDM. The aim of our study was to assess if PAPP-A and hCG values were different among pregnant women with and without GDM and respectively, to tested their place in the early GDM screening. MATERIAL AND METHODS: We conducted a retrospective, case-control study by reviewing the clinical database records of 662 pregnant women. The analysis includes the data for a two-year period. The patients included in the observation were divided into two groups - GDM group (n = 412) and Euglycemic group (n = 250). Early screening for GDМ between 9-12 weeks' gestation was performed in 173 of the women in the interventional group due to: registered fasting plasma glucose (FPG) above 5.1 mmol/L, obesity, macrosomia in previous pregnancies or family history for diabetes mellitus. The remaining 239 women underwent universal screening at 24-28 weeks' gestation. Mean serum levels of PAPP-A, hCG, FPG, and body mass index (BMI) were measured between 10-13 gestational weeks. Serum levels of PAPP-A and hCG are presented as multiples of the normal median (MoM), adjusted by maternal baseline characteristics and demographics. RESULTS: In patients who developed GDM during pregnancy, compared with the control group, we have found significantly lower MoM values of PAPP-A (p < 0.0001), higher levels of FPG (р < 0.0001) and higher BMI (р < 0.0001). Median hCG MoM was similar in both group of pregnant women. CONCLUSION: Our findings suggest that low-normal to low reference range values of PAPP-A might be associated with higher risk for GDM. PAAP-A levels can be used as an additional factor to recommend early screening for GDM.

Insulin-induced Lipoatrophy in a Patient on Insulin Analogue Therapy: a Case Report.

Insulin-induced lipoatrophy is a rare skin complication in patients with diabetes mellitus. It is characterized primarily by localized subcutaneous atrophy of the fatty tissue at the site of frequent insulin injection. We report a clinical case of a 38-year-old woman with lipoatrophy, developed during treatment with insulin analogues. Lipoatrophic zone formation began 3 months after the treatment was initiated. A lipoatrophic defect developed on the thighs and the upper outer arms, resulting from repeated insulin injections at the same site. Regarding lipoatrophic areas, treatment with topical administration of corticosteroids was attempted but without a significant clinical effect. The best prevention from lipoatrophy development is education of patients regarding rotation of insulin injection sites and more frequent needle change.

Autoimmune Polyglandular Syndrome Type 2 and Pregnancy.

Autoimmune polyglandular syndromes are combinations of various endocrine and nonendocrine autoimmune diseases, as well as the presence of elevated organ-specific antibody titers. We present a clinical case of a 41-year-old pregnant patient with type 2 autoimmune polyglandular syndrome, combining Addison's disease, Hashimoto's thyroiditis and hypogonadism. The pregnancy was achieved after the use of assisted reproductive technology. During the pregnancy the patient was strictly monitored. Glucocorticoid and mineralocor-ticoid replacement therapy was adjusted according to the electrolyte profile and general condition of the patient. Management during pregnancy was difficult due to fluctuations in electrolyte levels, thyroid hormones and orthostatic manifestations. Prior to delivery adrenal crisis occurred, but the condition was successfully managed. No complications were reported for the mother and the newborn.

Written Health Education Materials for Women with Gestational Diabetes Mellitus - Evaluation of Usefulness and Patients' Satisfaction.

BACKGROUND: Written health educational materials are an integral part of the treatment process. Because of the constantly increasing gestational diabetes mellitus (GDM) global rate, pregnant women require accessible, easy-to-understand and evidence-based medical information about this pregnancy complication. AIM: To adapt and elaborate printed educational materials on GDM and to evaluate the usefulness of the produced training materials and pregnant women's satisfaction. MATERIALS AND METHODS: The present study implemented a methodological approach covering three phases: (1) systematic literature review; (2) compilation of printed educational materials for pregnant women with GDM; (3) evaluation of the usefulness and satisfaction with the produced educational materials through a focus group consisting of pregnant women. A seven-item self-administered feedback questionnaire was adopted for evaluation of patient satisfaction after the use of educational materials. RESULTS: An educational manual was developed in compliance with the main requirements for effectiveness of educational materials referring to content, structure, language, layout and illustrations. The usefulness of the educational manual and patient satisfaction were evaluated by a sample group of 20 women with GDM. Approximately 95% agreed or strongly agreed that the information in the educational manual was useful. The patients' assessment of the understanding and readability of the written materials showed a satisfaction rate of 85%. The overall assessment for the educational materials was very high - excellent (65%), very good (30%) and good (5%). CONCLUSION: The provision of educational materials on GDM can enhance pregnant women's health literacy as well as their responsibility, motivation and attitude to their personal health.

Regulatory Requirements for Food Supplements in the European Union and Bulgaria.

Data provided by the European Commission show that public expenditures for food supplements have been constantly increasing over the last decade. The aim of the present study was to analyze the major food supplements regulations in the European Union and in Bulgaria. Relevant publications were searched and found in MEDLINE/PubMed, Scopus Database, Web of Knowledge, and in Internet-based search with predefined keywords. Numerous authors support the opinion that there is a real risk that low quality products may be distributed in countries with poor production control. Bulgarian national legislation have 6 regulations with different legal force for provision of healthy and safe food supplements on the market. Currently, the European Community is concerned about food products, including FS, launched on the market because the citizens require reliable protection of their health. This concern provoked the European Parliament and the Council to undertake a number of legislative initiatives in the field of production and control of food products. It is necessary to set more precise quality and safety criteria in future strategies associated with those products.