Abstract

Introduction

Vaginal bleeding is a common complication during pregnancy and may contribute to adverse pregnancy outcomes. This study aimed to evaluate the effect of first trimester bleeding on newborns Apgar scores.

Methods

A retrospective study was conducted on pregnant women who delivered at Shahid Sadoughi hospital in Yazd, Iran, between 2022 and 2023. Only singleton, nulliparous, non-diabetic women were included. Participants were divided into two groups: the exposure group (Bleeding Group) and control Group (Non-Bleeding Group), based on archived records. Apgar scores recorded at the first and fifth minutes after birth in newborns file were compared between groups.

Results

A total of 992 women were included, with 218 in the exposure and 774 in the control groups. The incidence of a first-minute Apgar score <7 was significantly higher in the bleeding group compared to controls (22.5% vs. 6.2%, p = 0.02). However, there was no significant difference in five-minute Apgar scores between groups.

Conclusion

This study demonstrated a positive association between first-trimester vaginal bleeding and a low first-minute Apgar score in newborns.

Introduction

The first trimester of pregnancy is a crucial period of fetal development, during which the body undergoes significant physiological changes to support the growing baby [1]. Maternal and fetal well-being are closely interconnected, and multiple factors influence fetal growth and metabolic programming.

First trimester bleeding defined as vaginal bleeding occurring between conception and 12 weeks of gestation. It is common and affecting between 16 - 25% of all pregnancies and often causes anxiety for both patients and clinicians [2-4]. Although many pregnancies with first-trimester bleeding progress without complication, emerging evidence suggests an increased risk of neonatal complications later in pregnancy [5,6]. The Apgar score, developed by Dr. Virginia Apgar in 1952, is a rapid and reliable method of assessing newborn condition and clinical status immediately after delivery [7-9]. The score is reported at one and five minutes after birth and, if below 7, at five-minute intervals up to 20 minutes [10]. Approximately 1% of low-risk live births have a five-minute Apgar score below 7, which is associated with a significantly higher risk of neonatal morbidity and mortality [11]. Low Apgar scores have also been linked to long-term adverse outcomes such as epilepsy, cerebral palsy, and developmental delays [12-14].

Numerous studies have investigated the relationship between first-trimester bleeding and neonatal health. Some of these studies indicate a correlation between first-trimester bleeding and low Apgar scores at the first and fifth minutes after birth [5,15-17]. Conversely, other studies have reported that first-trimester bleeding has no effect on newborn Apgar scores [18-21].

Several studies have explored the association between first-trimester bleeding and neonatal outcomes, with mixed results. Some found a correlation between early bleeding and low Apgar scores [5,15–17]. The others reported no significant relationship [18–21]. Some evidence suggests that only when bleeding results in complications such as intrauterine growth restriction (IUGR), preterm birth, or low birth weight does it significantly affect neonatal Apgar scores [5,22,23].

This study aims to further investigate the relationship between first-trimester bleeding and neonatal Apgar scores.

Methods

Study design and setting

This study was designed as a retrospective study. Data were collected from archived files at the hospital and medical records of pregnant individuals who delivered at Shahid Sadoughi hospital in Yazd, Iran, during one year.

Inclusion criteria

This study included singleton pregnancies that resulted in the delivery of live newborns at or beyond 37 weeks of gestation, with a birth weight greater than 2500 grams.

Exclusion criteria

Pregnancies were excluded if there were fetal anomalies, chronic maternal diseases such as diabetes mellitus, hypertension, renal, cardiac, or endocrine disorders, or any history of smoking or drug abuse. Additional exclusions included surgical conditions during pregnancy, multiple gestations, placental abruption or placenta previa in the later trimesters, and cases with incomplete medical records.

Grouping and data collection

Participants were categorized into two groups: an exposure group, consisting of pregnancies complicated by first-trimester vaginal bleeding, and a control group, comprising pregnancies without first-trimester bleeding. All included women were under 40 years of age. Demographic characteristics such as occupation, economic status, educational level, and maternal body mass index (BMI) were obtained. Clinical data were extracted from archived hospital records and patients' files, including obstetric history and detailed documentation of any first-trimester bleeding episodes. First-trimester vaginal bleeding was defined as bleeding occurring before 12 weeks of gestation in the presence of a closed cervix and a viable intrauterine pregnancy. Newborn outcomes, including Apgar scores at one and five minutes, were also retrieved from medical records. An Apgar score <7 at either time point was considered low, with scores classified as normal (>7), low (5–7), or very low (<5).

Statistical analysis

Data were analyzed using SPSS version 20. Continuous variables were compared using the t-test, while categorical variables were assessed using the chi-square test. A p-value of <0.05 was considered statistically significant.

Results

A total of 992 term singleton pregnancies were included in the analysis, comprising 218 women in the exposure (bleeding) group and 774 in the control group. Maternal and neonatal characteristics of both groups are presented in (Table 1).

Newborns in the bleeding group had a significantly higher proportion of first-minute Apgar scores <7 compared with the control group (22.5% vs. 6.2%, p = 0.02). Although five-minute Apgar scores <7 were also more common among the bleeding group (8.7% vs. 6.7%), this difference did not reach statistical significance (p = 0.6) (Table 2).

Women who experienced bleeding lasting more than two days had a greater frequency of low first-minute Apgar scores (65.3%) than those with shorter-duration bleeding (36.7%); however, this trend was not statistically significant (p = 0.06). Similarly, multiple bleeding episodes were associated with a higher proportion of low Apgar scores compared with single episodes, but without statistical significance (p = 0.07) (Table 3).

The mean birth weight of newborns was 2891 ± 539 g. While low birth weight was more common in the bleeding group, the difference was not statistically significant (Table 4). Overall, these findings suggest that first-trimester vaginal bleeding is associated with an increased risk of a low first-minute Apgar score at birth.

Discussion

This study found a significant association between first-trimester vaginal bleeding and low one-minute Apgar scores. The Apgar score is a key indicator of neonatal health, and lower values often reflect perinatal distress and risk of complications such as hypoxic-ischemic encephalopathy and NICU admission [10,12].

One of the most significant findings in this study was Neonates born to mothers with first-trimester bleeding were more likely to have a one-minute Apgar <7 (22.5% vs. 6.2%, p = 0.02). This finding is consistent with previous research suggesting that early pregnancy bleeding may compromise fetal growth and lead to neonatal distress [5,6,15-17,24].

Karimi et al. reported in their meta-analysis that vaginal bleeding during pregnancy is a risk factor for adverse outcomes, including low Apgar scores and preterm birth [5]. Bever et al. found that first-trimester bleeding was linked to altered fetal growth patterns, which can contribute to neonatal distress and first minute low Apgar [6]. Some of these studies indicate a correlation between first-trimester bleeding and low Apgar scores at one and five minutes of birth [15-17, 24].

The underlying mechanism may involve placental dysfunction. Early bleeding may indicate subchorionic hematoma or implantation abnormalities, which can reduce placental efficiency and lead to fetal hypoxia. Gaillard et al. [1] reported that placental dysfunction adversely affects fetal growth and development, potentially manifesting as low Apgar scores. Maternal inflammation during early bleeding episodes may also negatively influence fetal development [15].

Although, some studies conversely have reported that first-trimester bleeding has no effect on newborn Apgar scores [18- 21], therefore, it seems that more studies are needed in this objective.

The absence of a significant difference in five-minute Apgar scores in our study the groups (bleeding: 8.7% vs. control: 6.7%, p = 0.6) suggests that prompt neonatal care and resuscitation may mitigate initial distress. This finding is consistent with Chen et al, who suggested that while low five-minute Apgar scores are predictive of long-term adverse outcomes, short-term resuscitation efforts often improve neonatal condition [11]. Current guidelines from the American Academy of Pediatrics recommend that neonates with low Apgar scores receive immediate and thorough evaluation to mitigate the risks associated with potential perinatal asphyxia [7].

Longer or recurrent bleeding episodes appeared to increase the risk of low Apgar scores, though not significantly. Chandrakala and Reshmi similarly noted that recurrent bleeding episodes often indicate placental dysfunction and can contribute to perinatal morbidity [24].

Although low birth weight was more common in the bleeding group, the difference was not statistically significant, differing from studies by Karimi et al, and Velez et al, possibly due to differences in population size and inclusion criteria [5,22]. The discrepancy may be attributed to variations in study populations, sample sizes, and differing criteria for defining low birth weight.

Conclusion

This study underscores the importance of vigilant prenatal monitoring in pregnancies affected by early first-trimester bleeding. Further investigations are required to identify predictors of adverse neonatal outcomes and to develop preventive measures that may enhance newborn health.

Declarations

Conflicts of interest: The authors have no conflicts of interest to disclose.

Ethical approval: The study was approved by the Institutional Ethics Committee and utilized data obtained from hospital archives.

Patient consent (participation and publication): Was obtained from all participants prior to completing the questionnaire, and participants were assured of confidentiality and anonymity.

Funding: The present study received no financial support.

Acknowledgements: The authors thank the residents of the Obstetrics and Pediatrics Departments at Shahid Sadoughi University of Medical Sciences, Yazd, Iran, for their assistance in data collection, and the Department of Statistics for support with data analysis.

Authors' contributions: LS Contributed to drafting the manuscript and critically revising its content, and approved the final version prior to submission. AJ Responsible for data acquisition, study conception and design, as well as data analysis and interpretation. All authors read and approved the manuscript.

Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data.

Data availability statement: Not applicable.

Abstract

Introduction

Among the most frequently used anticoagulants in hematological testing are tetra-acetic acid (EDTA), sodium citrate, and sodium heparin. However, there is a noticeable gap in literature concerning the effects of these anticoagulants on hematological parameters specifically in humans. This study aims to assess the effectiveness of EDTA, sodium citrate, and sodium heparin for conducting complete blood count (CBC).

Methods

This cross-sectional study conducted at Smart Health Tower from January to April 2024 involved 250 participants who underwent CBC using K2EDTA, sodium citrate, and sodium heparin. The acquired data were analyzed using SPSS, with a significance level of p < 0.05, employing Intra-class correlation coefficient and one-way ANOVA to assess consistency and agreement among anticoagulants.

Results

A total of 250 participants, with 138(55.2%) males and 112(44.8%) females, underwent CBC testing with di potassium EDTA(K2EDTA), sodium citrate, and sodium heparin. Comparing K2EDTA with sodium heparin showed comparable values in 14 out of 23(60.87%) CBC parameters. Using K2EDTA as the standard, citrate showed perfect or substantial agreement in assessing 8 out of 23 CBC parameters (34.78%). Regarding the comparison of anticoagulants to K2EDTA to determine their agreement levels while sodium heparin was accurate and precise in 13(56.52%) parameters.

Conclusion

Citrate was found to be a less reliable anticoagulant for CBC estimation compared to K2EDTA, potentially leading to inaccurate readings. On the other hand, sodium heparin showed comparable performance to K2EDTA, making it a suitable alternative under specific conditions.

Introduction

The Complete Blood Count (CBC) is a widely requested blood test by clinicians, assessing the total quantities and characteristics of cellular constituents within the bloodstream. The CBC parameters include red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). This comprehensive assessment includes determining the total and differential count of WBCs, also measuring RBC count, hemoglobin (HGB) levels, and hematocrit (HCT), as well as their indices such as mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and red cell distribution width (RDW). Additionally, CBC evaluates platelet (PLT) count indices [1,2]. A CBC serves as an important diagnostic tool for assessing human health, detecting congenital abnormalities, and identifying functional changes due to various pathological factors [3]. Its findings can reveal various conditions such as infections with elevated WBC counts, leukemia with abnormal WBC counts, anemia with low HGB levels, and liver cirrhosis with reduced PLT counts. Recent studies suggest that specific combinations of CBC components, along with derived secondary results, can predict risks of different diseases like cardiovascular disease, cancer, type 2 diabetes, and metabolic syndrome [1,2].

It's widely recognized that collection and sampling of blood, laboratory techniques and storage conditions, and the choice of anticoagulant can substantially impact the outcomes derived from hematological analysis, especially CBC results [4]. Among the various anticoagulants used for both sample collection and routine laboratory analysis, the most commonly utilized ones in hematology are ethylene diamine tetra acetic acid (EDTA), citric acid salts, sodium and lithium oxalates, and heparin [5,6].

The National Committee for Clinical Laboratory Standards has suggested using EDTA for CBC due to its ability to preserve cell structure [7]. However, limited evidence exists on the effects of other anticoagulants on CBC parameters among animal species. Among humans, heparin is typically avoided for blood smears and WBC counts due to staining and clotting issues, respectively. Conversely, EDTA is considered unsuitable for erythrocyte osmotic fragility assessment and may cause cell damage if overused [8].

The majority of studies documented in existing literature have focused on evaluating the impacts of different anticoagulants on CBC results or its specific components across diverse animal species. The current study aims to estimate variations in CBC parameters using different anticoagulants, employing dipotassium EDTA(K2EDTA), sodium citrate, and sodium heparin, among humans to evaluate their effectiveness.

Methods

Study Design, population, and criteria

This cross-sectional laboratory-based study was conducted at Smart Health Tower from January to April 2024. Prior to participation, all individuals were thoroughly briefed about the study and required to provide informed written consent. The study included a total of 250 participants, all of whom underwent complete blood count tests utilizing K2EDTA, sodium citrate, and sodium heparin as anticoagulants. The study population consisted of patients attending Smart Health Tower, representing both genders without any gender bias. Inclusion was restricted to those who had visited the facility, while individuals or their guardians ( in case of minors) who declined to provide consent were excluded from the study.

Determination of the sample size

The effective sample size was determined using G*Power statistic 3.1.9.7, employing linear multiple regression as the statistical test with a two-tailed approach. With an effective sample size of 0.35, an α error probability of 0.01, and a statistical power of 0.99, along with a predictor value of 1, the minimum required sample size was 158. Therefore, a sample size of 250 was utilized for the comparison in CBC parameters between these three different anticoagulants.

Sample collection and statistical analysis

Trained health workers collected blood samples from participants using sterile syringes and needles, drawing 5 mL from either the median cubital or prominent forearm vein. The samples were distributed as follows: 1.8 mL into sodium citrate tubes and 1.6 mL into K2EDTA and sodium heparin tubes. After gentle mixing, complete blood counts (CBC) were analyzed with the Medonic M51 automated hematology analyzer within 3 to 6 hours post-collection. Tube characteristics are detailed in Table 1. Various hematological parameters were assessed, including WBC, percentages of neutrophils, lymphocytes, monocytes, eosinophils, basophils, as well as RBC, HCT, HGB, MCV, MCHC, RDW-SD, PLT, MPV, PDW, PCT, and PLCR. Participant demographics, such as age and gender, were also recorded. Data were initially processed in Microsoft Excel 2019 for accuracy and completeness before being transferred to SPSS version 25.0 and MedCalc version 20 for statistical analysis. Intra-class correlation coefficient (ICC) analysis was conducted to evaluate consistency among the three anticoagulants, with interpretations as follows: <0.50 for poor consistency, 0.50-0.75 for moderate, 0.75-0.90 for good, and >0.90 for excellent consistency. A p-value of <0.05 was considered significant. One-way ANOVA assessed variations in CBC parameters among samples collected in K2EDTA, sodium citrate, and sodium heparin tubes. Additionally, the concordance correlation coefficient (CCC) was used to evaluate agreement, with K2EDTA as the standard, and interpreted as follows: ≥0.99 for almost perfect agreement, 0.95-0.99 for significant agreement, 0.90-0.95 for moderate agreement, and <0.90 for poor agreement [9].

Results

Among the 250 participants involved, 138 (55.2%) were male, and 112 (44.8%) were female. The participants had an average age of 41.20 ± 16.51 years (5-91). Consistency in CBC results using sodium heparin, K2EDTA, and sodium citrate indicated excellent consistency in the determination of WBC, %Neu, %Lymph, Neu, Lymph, RBC, HGB, HCT, MCV, MCH, MCHC, RDW-SD, MPV, PDW, and PLCR among these anticoagulants with ICC >0.90 (Table 2). 

Regarding variation in CBC parameters using K2EDTA, sodium citrate, and sodium heparin, no statistically significant variation was found in the median %Lymph, Eos, MCV, and MCH among these three different anticoagulants (Table 3).  

Regarding variation in estimation of CBC parameters using the results of two anticoagulated blood such as K2EDTA-sodium citrate, K2EDTA-sodium heparin, sodium citrate-sodium heparin, the results of the comparison of K2EDTA-sodium citrate indicated comparable results in median %Neu, %Lymph, %Eos, Neu, Bas, MCV, MCH, and MCHC with a p-value of ≥0.05. Comparison of K2EDTA-sodium heparin results indicated comparable results in median WBC, %Lymph, %Eos, Neu, Lymph, RBC, HGB, HCT, MCV, MCH, RDW-SD, MPV, PDW, and PLCR with a p-value of ≥0.05. In comparing the results of CBC between sodium citrate-sodium heparin, the result indicated a nonsignificant difference in median WBC, %Lymph, %Eos, Lymph, MCV, MCH, RDW-SD, and PCT (Table 4).

The agreement levels between different anticoagulants, using K2EDTA as the standard, were evaluated. Sodium citrate showed perfect agreement in assessing MCV and MCH (CCC = 0.990) but displayed significant agreement in determining WBC, %Neu, %Lymph, Neu, Lymph, and Eos (CCC between 0.95 and 0.99). Moderate agreement was observed in assessing MCHC (CCC = 0.929), while poor agreement was found in all other parameters with CCC<0.90. Similarly, sodium heparin demonstrated perfect agreement in determining MCV (CCC=0.994) and MCH (CCC=0.990), with substantial agreement in other parameters such as WBC, %Lymph, Neu, Lymph, RBC, and HGB (CCC between 0.95 and 0.99), but poor agreement in parameters with CCC<0.90. Regarding the comparison of K2EDTA and sodium citrate, citrate was highly precise and accurate in the estimation of WBC, %Neu, %Lymph, Neu, Lymph, Eos, MCV, MCH, and MCHC. While comparing sodium heparin to K2EDTA, it was highly precise in the estimation of WBC, %Neu, %Lymph, Neu, Lymph, Eos, RBC, HGB, HCT, MCV, MCH, MCHC, and PLCR (Table 5).

Discussion

The choice of anticoagulants and storage time significantly affect blood sample analysis [10]. In a study by Akorsu et al. involving 55 healthy individuals, consistency in blood parameters across three anticoagulants was observed: K3EDTA, sodium citrate, and lithium heparin [3]. Similarly, a current study utilized K2EDTA, sodium citrate, and sodium heparin, finding excellent consistency in various blood parameters, with ICC values exceeding 0.90.

Regarding variation in CBC parameters using different anticoagulants, in a study which is conducted on 30 clinically healthy dogs from different breeds, no significant variation between sodium citrate and K3EDTA was found in 4 out of 8 CBC parameters (50%) including HGB, HCT, PLT, and PCT [11]. Similarly, in a study conducted on humans, in which variation in the estimation of CBC parameters was evaluated using three different anticoagulants, namely, K3EDTA, sodium citrate, and lithium heparin, no statistically significant difference was observed in 5 out of 14 CBC parameters (35.7%) including MCV, MCH, MCHC, %Lymph, and %Neu among the three anticoagulants examined [3]. In the present study, regarding variation in CBC parameters using K2EDTA, sodium citrate, and sodium heparin, no statistically significant variation was found in 4 out of 23 CBC parameters (17.40%) including %Lymph, Eos, MCV, and MCH among these three different anticoagulants. The significant variations observed in other CBC parameters underscore the need for careful consideration when selecting anticoagulants, particularly in clinical settings where precise and consistent CBC measurements are crucial for accurate diagnosis and monitoring of conditions [12].

In a study of 50 healthy dogs comparing EDTA and sodium citrate, no comparable results were found among 9 CBC parameters, suggesting citrate may lead to inaccurate results compared to EDTA [13]. Another study of 55 healthy individuals comparing heparin and citrate revealed significant differences in 5 out of 14 CBC parameters (35.71%), with the remaining parameters showing variations. Similar patterns were observed when comparing citrate to EDTA. Comparing heparin to K3EDTA showed significant variations in three parameters (21.43%) [3]. In the current study, comparing K2EDTA to sodium citrate showed similar results in 8 out of 23 CBC parameters (34.78%), while comparing K2EDTA to sodium heparin showed comparable values in 14 out of 23 CBC parameters (60.87%).

Comparing PLT results between K2EDTA and sodium citrate with sodium heparin, significantly lower PLT counts were found in the latter two in the current study, contradicting findings in existing genuine literature [14-16]. One study suggested that citrate's strong platelet activation in sick animals may lead to decreased PLT counts due to platelet clumping [17]. Additionally, lower HGB and HCT values were observed in citrated blood samples compared to EDTA, consistent with previous studies [3,11]. This discrepancy may be attributed to citrate's interference with HGB oxidation, resulting in higher HGB levels in EDTA samples.

The CBC is commonly conducted on venous blood specimens anticoagulated with EDTA. Among various EDTA subtypes, the dipotassium salt form, K2EDTA, is endorsed by the International Council for Standardization in Hematology as the preferred anticoagulant for blood cell enumeration and sizing [7]. The study evaluated agreement levels between different anticoagulants, using K2EDTA as the standard. Sodium citrate showed substantial agreement in 8 out of 23 CBC parameters (34.78%), including MCV, MCH, WBC, %Neu, %Lymph, Neu, Lymph, and Eos. Similarly, sodium heparin demonstrated substantial agreement in determining MCV, MCH, WBC, %Lymph, Neu, Lymph, RBC, and HGB. These findings align with previous literature, which indicated substantial agreement with heparin in assessing 4 out of 14 CBC parameters (28.57%), including RBC, HGB, HCT, and MCH [3].

Conclusion

Citrate was found to be a less reliable anticoagulant for CBC estimation compared to K2EDTA, potentially leading to inaccurate readings. On the other hand, sodium heparin showed comparable performance to K2EDTA, making it a suitable alternative under specific conditions.

Declarations

Conflicts of interest: The authors have no conflicts of interest to disclose.

Ethical approval: The study was approved by the Institutional Ethics Committee and utilized data obtained from hospital archives Ethical Approval for this study was obtained from the Ksciens ethical committee (Approval Number 43. 2025).

Patient consent (participation and publication): Written informed consent was obtained from all patients (or their legal guardians, where applicable) for participation in the study and for the publication of all associated clinical information and images.

Source of Funding: Star Lab Company.

Role of Funder: The funder remained independent, refraining from   involvement   in   data   collection, analysis, or   result formulation, ensuring unbiased research free from external influence.

Acknowledgements: Not applicable.

Authors' contributions: RQS and SQO were major contributors to the conception of the study, as well as to the literature search for related studies. DAH and AMM were involved in the literature review and the writing of the manuscript. SLE, HAY, HSA and MTT were involved in the literature review, the design of the study, the critical revision of the manuscript, and the processing of the tables.  QOS and AMM confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data.

Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abstract

Introduction

Hypothyroidism is a common endocrine disorder, in which the management involves daily intake of thyroxine. However, adherence to a daily medication regimen poses a substantial challenge for many patients. The current study aims to assess the efficacy of once and twice-weekly thyroxine regimen for the management of hypothyroidism.

Methods

This was a single-center cohort study involving hypothyroid patients that was conducted over three years. In this study, standard daily, once and twice-weekly thyroxine dosing regimens were used to treat the patients. The effectiveness of the three dosage regimens was ascertained by whether the patients achieved a euthyroid state after six months of therapy.

Results

In total, 328 hypothyroid cases due to thyroiditis were included in this study. The average age of the cases was 42.7 years (14-92). Before thyroxine therapy, in the standard daily regimen group, the median level of TSH was 15.4 μIU/mL (IQR 23.1), in the once-weekly regimen group, the level was 9.2 μIU/mL (IQR 6.8), and in the twice-weekly regimen group, the level was 9.1 μIU/mL (IQR 7.3). After thyroxine intake and upon follow-up after 6 months, the TSH level decreased to 4.0 μIU/mL (IQR 3.7), 4.5 μIU/mL (IQR 4.9) and 4.2 μIU/mL (IQR 5.1) in the standard daily, once- and twice-weekly regimen groups, respectively.

Conclusion

Once and twice weekly thyroxine shows promise as strategies for managing hypothyroidism. However, variability in patients in response to weekly thyroxine needs to be taken into account.

Introduction

Hypothyroidism is a condition characterized by the inadequate production of thyroid hormones and represents a common endocrine disorder affecting a significant proportion of the global population [1]. The standard management of this condition typically involves daily administration of synthetic thyroxine to normalize thyroid hormone levels, thereby alleviating associated symptoms and metabolic disturbances. Daily thyroxine therapy regimen is well-established in clinical practice, with its efficacy extensively documented in the medical literature [1,2]. However, adherence to a daily medication regimen can be challenging for many patients. Factors such as the requirement to take the medication on an empty stomach, the necessary waiting period before the next meals or beverages, and potential drug interactions may contribute to inconsistent compliance. Suboptimal adherence to daily thyroxine therapy can significantly impair the management of hypothyroidism, resulting in inadequate control of thyroid function and poorer patient outcomes [3].

Recently, non-daily alternative dosing schedules, specifically once or twice-weekly thyroxine administration, have gained attention as potential strategies to improve adherence. Nevertheless, studies evaluating the efficacy of these regimens remain limited, and current evidence is insufficient to support changes in clinical practice. The current study aims to assess the efficacy of once and twice-weekly thyroxine dosing compared to standard daily administration for the management of hypothyroidism.

Methods

Study design

This was a single-center cohort study conducted at the head and neck center of Smart Health Tower, Sulaimani, Iraq, from January 2020 to January 2023. It involved the retrospective analysis of a series of hypothyroid cases to evaluate the efficacy of once and twice-weekly thyroxine regimens compared to standard daily dose. Written informed consent was obtained from the patients and the family of the patients.

Participation

Participants were individuals who visited the head and neck center for the treatment of hypothyroidism. Patients who had undergone thyroidectomy were excluded from the study to avoid confounding effects on thyroid function.

Treatment plan

Patients were assigned to one of three treatment groups based on the prescribed thyroxine regimen: daily, once-weekly, or twice-weekly. According to thyroid function tests and body weight, different daily and weekly doses were prescribed to the patients to reach euthyroidism, including 25, 50, 75, or 100 μg per day, or 100, 200, or 300 μg per week. Patients were followed for six months, and treatment effectiveness was determined by whether they achieved a euthyroid state, defined as a thyroid stimulating hormone (TSH) level between 0.4 and 4.2 μIU/mL.

Data collection and analysis

Data were extracted from the center’s medical database and included patient’s age, gender, marital status, occupation, chief complaint, thyroxine dosage, TSH pre-treatment, and TSH six months following therapy. All data were entered into an Excel spreadsheet (2016). Statistical analyses were performed using statistical package for social sciences (SPSS) version 25. Descriptive statistics were presented as means or medians (for non-normally distributed data), counts, and percentages. Univariate analyses were conducted to compare baseline characteristics (including age, gender, marital status, occupation, and chief complaint) and treatment outcomes between groups. Additionally, multivariate logistic regression analysis was performed to identify independent predictors of achieving normal TSH (0.4–4.2 μIU/mL) at six months. A p-value of less than 0.05 was considered statistically significant.

Results

In total, 328 hypothyroid cases due to thyroiditis were included in this study. The mean age of the cases was 42.7 years, ranging from 14 to 92 years. The majority of the cases were female, accounting for 303 individuals (92.4%). The most common presentation in all groups was weakness in 146 (44.5%) cases, followed by incidental finding in 81 (24.7%), and neck pain in 37 (11.3%). Overall, the first TSH mean (before therapy) was 20.8, while the second TSH mean (after treatment) was 5.1 (Table 1).

The median age was similar across the three groups, with 42.0 years (IQR 13.5) in the once-weekly group, 40.0 years (IQR 16.0) in the twice-weekly group, and 43.0 years (IQR 23.0) in the daily group (p = 0.061). Females predominated in all groups, accounting for 98% of the once-weekly group, 97.5% of the twice-weekly group, and 81.7% of the daily group, with a statistically significant difference (p < 0.001). Regarding occupation, the majority were jobless across all groups, but the daily group had a higher proportion of employed participants (9.2%) compared with the weekly groups (p < 0.001) (Table 2).

Before thyroxine therapy, in the once-weekly regimen group, the median value of TSH was 9.2 μIU/mL (IQR 6.8 μIU/mL), in the twice-weekly regimen group the level was 9.1 μIU/mL (IQR 7.3 μIU/mL), and in the standard daily dose group the median level was 15.4 (IQR 23.1 μIU/mL). After thyroxine intake and upon follow-up after six months, the TSH level decreased to 4.0 μIU/mL (IQR 3.7 μIU/mL), 4.2 μIU/mL (IQR 5.1 μIU/mL) and 4.5 μIU/mL (IQR 4.9 μIU/mL) in the standard daily, once- and twice-weekly regimen group, respectively (Figure 1) (Table 3). The outcome was statistically insignificant between groups. After six months of follow-up, 56.9% of patients in the daily regimen group, 43.0% in the once-weekly group, and 44.5% in the twice-weekly group achieved TSH levels within the normal reference range (Figure 2).

Compared to the daily treatment group, patients in the once-weekly group had an odds ratio (OR) of 0.659 (95% CI: 0.310–1.398, p = 0.277), and those in the twice-weekly group had an OR of 0.763 (95% CI: 0.363–1.602, p = 0.474), indicating no statistically significant difference in achieving normal TSH between the treatment regimens. Gender was not a significant predictor; males had an OR of 1.845 (95% CI: 0.439–7.751, p =0.403) compared to females. Age and baseline TSH similarly did not significantly influence the likelihood of achieving normal TSH (OR = 0.997, p = 0.801 and OR = 0.995, p = 0.317, respectively) (Table 4).

Discussion

Hypothyroidism can often occur as a result of thyroiditis or thyroidectomy to remove part of or the entire thyroid tissue [4-6]. The standard treatment for hypothyroidism involves daily administration of thyroxine, a synthetic form of the thyroid hormone. However, emerging evidence suggests that a weekly thyroxine regimen may offer several advantages in terms of patient convenience, treatment adherence, and potentially improved clinical outcomes [7]. Noncompliance with thyroxine is the most prevalent cause of poor hypothyroidism management, which is linked to the discomfort of taking the drug when fasting, waiting 60 minutes for the next meal or beverage, and avoiding other medications that may interfere with thyroxine absorption [8]. The feasibility of weekly thyroxine dosing lies in the pharmacokinetics of levothyroxine. It has a long half-life, with stable levels maintained in the bloodstream for several weeks. Additionally, the availability of thyroxine formulations that allow for extended release further supports the feasibility of weekly dosing [9].

One of the primary advantages of weekly thyroxine is the potential for enhanced patient convenience and improved treatment adherence. Daily medication regimens can be challenging for patients to adhere to consistently, leading to suboptimal management of hypothyroidism. Weekly thyroxine simplifies the dosing schedule, reducing the burden of daily medication intake [10]. Studies have shown that non-adherence to daily thyroxine therapy is common and can result in inadequate control of thyroid function. By reducing the frequency of dosing, weekly thyroxine may address the issue of non-adherence and improve the effectiveness of treatment in achieving target thyroid hormone levels and overall clinical outcomes [11].

There have been very few studies comparing daily versus weekly treatment of thyroxine in hypothyroid patients globally. Therefore, there is a crucial need to expand the current body of litrerature on this treatment strategy. According to one study, in today's world of busy lifestyles, when it is difficult for patients to take thyroxine on a strict schedule, once-weekly thyroxine administration gives an alternate option for treating hypothyroidism, particularly in patients whose compliance is a big concern [12]. Bornschein et al. found comparable results between daily and weekly dosing, with no hyperthyroidism in patients with weekly regimens [10]. Rangan et al. demonstrated in a case series of two patients that once-weekly thyroxine is an alternate treatment approach for noncompliant patients and remarked that once-weekly thyroxine is a safe treatment regimen [11]. Another study found that when compared to a daily dosage of thyroxine, once weekly thyroxine is an effective and safe long-term treatment option for individuals with poor management of hypothyroidism or apparent thyroxine resistance. With directly monitored once-weekly thyroxine, approximately three-quarters of such individuals are able to achieve TSH normalization [8]. According to Chiu et al., weekly thyroxine administration results in less suppression and greater overall TSH levels while keeping below the normal reference range as specified by worldwide treatment recommendations. It may be a viable option for hypothyroid individuals, especially if compliance is an issue [13].

Concerns have also been expressed that taking a big dose of once-weekly thyroxine may result in increased supraphysiologic levels of thyroxine in the first few days, which may have an unfavorable effect on cardiovascular function. It is also believed that by the sixth day of thyroxine administration, the efficacy of once-weekly thyroxine would have worn off, resulting in the recurrence of hypothyroid symptoms and swings in TSH levels [14]. Grebe et al. showed that, while weekly treatment was well tolerated, thyroid function tests showed significant hypothyroidism with an increase in TSH and a decrease in thyroxine before the next weekly prescription [15]. A meta-analysis of four trials including 294 participants evaluated the effect of once weekly thyroxine on TSH after 6 weeks of treatment. After 6 weeks of therapy, once weekly thyroxine patients had considerably greater serum TSH than standard daily thyroxine patients [14]. The results of the current study showed that once weekly and twice weekly thyroxine were almost equally effective as standard daily thyroxine in achieving and maintaining normal thyroid function. There were no significant differences between the three treatment groups.

This study has several limitations, including relatively small group sizes, a single-center design, and a short follow-up period of six months. Despite these limitations, the findings provide supportive evidence that may have implications for current clinical practice regarding thyroxine administration. Future research involving larger, multicenter cohorts with longer follow-up periods is warranted to validate and expand upon these results.

Conclusion

The comparison of once-daily, once-weekly, and twice-weekly thyroxine administration highlights the potential benefits of less frequent dosing for hypothyroidism management. While all regimens appear to maintain comparable efficacy and safety, the convenience and potential for improved adherence associated with less frequent dosing regimens are notable. However, patient response to weekly thyroxine can vary, and some individuals may require more frequent administration or may not be suitable candidates for weekly therapy. Additionally, infrequent dosing carries the risk of missed doses, which could compromise treatment effectiveness. Therefore, close monitoring of thyroid function and individualized dose adjustments are essential to optimize outcomes. Long-term studies are needed to evaluate the sustained efficacy, safety, and patient satisfaction with weekly thyroxine regimens. Further research comparing different thyroxine formulations for weekly dosing and assessing their impact on specific populations, such as pregnant women or patients with comorbidities, would be valuable.

Declarations

Conflicts of interest: The authors have no conflicts of interest to disclose.

Ethical approval: Ethical approval for this study (Ethical Committee No: 95) was provided by the Ethical Committee of School of Medicine-University of Sulaimani.

Patient consent (participation and publication): Written informed consent was obtained from all patients and/or their legal guardians for participation in this study and for the publication of any accompanying images, clinical information, and other data included in the manuscript.

Source of Funding: Smart Health Tower.

Role of Funder: The funder remained independent, refraining from   involvement   in   data   collection, analysis, or   result formulation, ensuring unbiased research free from external influence.

Acknowledgements: None to be declared.

Authors' contributions: AMS and SFA were major contributors to the conception of the study, as well as to the literature search for related studies. MNH, SHH and HAH were involved in the literature review and the writing of the manuscript. ASM, MMA, HMZ, YAS, SHA, HOB, MAA and SHA were involved in the literature review, the design of the study, the critical revision of the manuscript, and the processing of the tables.  AMS and MNH confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data.

Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abstract

Background

Diagnosis of neurogenic thoracic outlet syndrome (nTOS) is hindered by symptom overlap with cervical radiculopathy, carpal tunnel syndrome, or psychosomatic disorders. This challenge is further compounded by often normal imaging and electrodiagnostic findings, resulting in prolonged diagnostic suffering encompassing emotional, financial, and social burdens.

Objectives
This first qualitative study explores narratives from 25 diagnosed women initially prescribed physiotherapy: (1) identify key themes related to diagnostic challenges; (2) examine the psychological and emotional impact of diagnostic delay; and (3) propose a patient-centered diagnostic framework.

Methods

Qualitative descriptive design using semi-structured interviews (20-30 minutes) with purposive sampling from a TOS clinic (inclusion: confirmed nTOS, >1-year symptoms, no prior surgery; Data saturation was achieved after 22 interviews). Braun and Clarke’s reflexive thematic analysis generated 1,247 inductive codes, which were organized into four themes and twelve subthemes. NVivo software was used for data management. Member checking was conducted, and reporting followed COREQ guidelines. Ethical approval was obtained, and participant anonymity was preserved through pseudonyms.

Results

Four overarching themes emerged: (1) Fragmented Diagnostic Odyssey, characterized by multiple referrals (mean six clinicians per patient) and substantial out-of-pocket costs (USD 1,000–1,500); (2) Cascade of Misdiagnoses, including somatic mimics, invasive investigations, and prolonged incorrect treatment; (3) Social and Familial Invalidation, involving medical dismissal and pressure toward psychiatric explanations; and (4) Profound Emotional Suffering, with isolation and hopelessness identified in 84% of transcripts. A conceptual model was developed to illustrate the cumulative diagnostic journey.

Conclusion

Neurogenic thoracic outlet syndrome is associated with multilayered diagnostic and social invalidation consistent with the stigma of invisible illness. Improving outcomes requires enhanced clinician awareness of nTOS-specific red flags, validation of patient narratives, and multidisciplinary diagnostic pathways to reduce delays, prevent iatrogenic harm, and alleviate psychological distress.

Introduction

Neurogenic thoracic outlet syndrome (nTOS) is characterized by compression of the brachial plexus as it traverses the thoracic outlet, causing upper extremity pain, numbness, paresthesia, and variable degrees of weakness. The condition predominantly affects young women, often triggered by repetitive overhead activities, postural strain, or antecedent trauma. Despite its clinical relevance, nTOS remains one of the most diagnostically challenging peripheral nerve compression syndromes due to its heterogeneous and fluctuating presentation [1,2].

Clinical recognition is often delayed, as symptoms overlap substantially with more prevalent conditions such as cervical radiculopathy, carpal tunnel syndrome, peripheral neuropathies, and functional or psychosomatic disorders. The absence of definitive radiological or electrodiagnostic findings in many patients further compounds diagnostic uncertainty, contributing to prolonged diagnostic latency that may span several years [1,2]. Consequently, patients frequently undergo multiple inconclusive investigations and consultations before receiving an accurate diagnosis [1,2].

Beyond physical morbidity, individuals with nTOS experience a form of diagnostic suffering, encompassing emotional distress, financial strain, social disruption, and erosion of trust in healthcare systems. Recurrent symptom invalidation and misattribution may intensify anxiety, frustration, and feelings of marginalization. This experience closely parallels Bury’s concept of biographical disruption in chronic illness, whereby delayed or contested diagnoses fracture personal identity, future planning, and the patient–clinician relationship [3,4].

The present study seeks to illuminate these underexplored qualitative dimensions through in-depth narratives from 25 diagnosed women, all of whom were initially prescribed physiotherapy as first-line management. The study objectives are threefold: (1) to identify recurring themes related to diagnostic challenges and healthcare encounters; (2) to explore the psychological and emotional impact of prolonged diagnostic trajectories; and (3) to propose a patient-centered diagnostic framework that integrates biomedical assessment with experiential and psychosocial dimensions.

Methods

Study design

A qualitative descriptive study design with interpretive orientation was employed using semi-structured conversations to explore participants lived experiences of neurogenic thoracic outlet syndrome, this approach was selected to capture rich, first-person accounts while remaining close to participants’ language and meanings. The study was conducted and reported in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist [5].

Participants and sampling

Purposive sampling recruited 25 female patients from a TOS specialty clinic. Inclusion: confirmed nTOS diagnosis, physiotherapy as initial treatment, symptom duration >1 year. Exclusion: surgical intervention prior to study. Saturation achieved after 22 interviews, with 3 additional for confirmation. Inclusion criteria were: (1) a confirmed diagnosis of neurogenic thoracic outlet syndrome, (2) initiation of physiotherapy as first-line management, and (3) symptom duration exceeding one year. Patients who had undergone surgical intervention prior to study enrollment were excluded. Data saturation was reached after 22 interviews, with three additional interviews conducted to confirm thematic completeness and stability.

Data collection

One-on-one conversations (20–30 minutes) in a private clinic room to ensure confidentiality and participant comfort A semi-structured interview guide was used to explore diagnostic trajectories, experiences of misdiagnosis, emotional and psychological impact, and social responses to symptoms. Sample prompts included: “Can you walk me through your journey to receiving a diagnosis?” and “How did family members or healthcare providers respond to your symptoms?” (Table 1). All interview were audio-recorded with participants’ consent and transcribed verbatim, yielding approximately 450 pages of textual data.

Data analysis

Braun and Clarke's (2006) reflexive thematic analysis in six phases (6):

1.    Familiarization: Repeated, immersive reading of transcripts to gain an overall understanding of the data.
2.    Coding: Inductive line-by-line coding was performed, generating 1,247 initial codes.
3.    Theme Generation: Collating into 4 main themes, 12 subthemes.
4.    Review: Preliminary themes were reviewed and refined through member checking with ten participants.
5.    Definition: Themes were clearly defined, refined, and supported by illustrative patient quotations.
6.    Reporting: Final themes were synthesized and presented using verbatim extracts to preserve participants’ voices.

NVivo 14 used for management. Methodological rigor and trustworthiness were enhanced through maintenance of an audit trail, thick description, reflexive journaling, and transparency regarding researcher positioning; the researchers declared no personal or clinical conflicts of interest related to thoracic outlet syndrome.

Ethical considerations

The study was conducted in accordance with ethical principles for human research. Written informed consent was obtained from all participants prior to participation. Pseudonyms were assigned to protect confidentiality. Participants were provided with debriefing following the conversations and offered referral resources for psychological or clinical support if needed.

Results

Analysis of interviews with 25 participants (coded P1–P25) yielded four overarching themes, each comprising related subthemes supported by illustrative verbatim quotations.

Theme 1: Fragmented Diagnostic Odyssey

Participants described a prolonged and exhausting diagnostic trajectory characterized by repeated referrals and inconclusive investigations across multiple medical specialties. On average, participants reported consulting approximately six physicians prior to receiving a diagnosis of neurogenic thoracic outlet syndrome.

Subtheme 1.1: Endless Investigations

"I have done hundreds of investigations; each doctor tells me a different diagnosis." (P7) "I cannot count how many doctors I visited; no one told me you have nTOS." (P14) These accounts highlight a cycle of uncertainty in which repeated testing failed to yield diagnostic closure.

Subtheme 1.2: Financial and Time Toll

The diagnostic delay was accompanied by substantial financial and temporal burden. Participants reported out-of-pocket expenditures ranging from approximately USD 1,000 to 1,500, in addition to lost workdays and prolonged functional impairment.

Theme 2: Cascade of Misdiagnoses

Symptom overlap with other neurological, musculoskeletal, and systemic conditions frequently resulted in misdiagnosis and inappropriate interventions.

Subtheme 2.1: Somatic Mimics: Several participants underwent unnecessary or unrelated treatments based on incorrect attribution of symptoms:

"I extracted three teeth; they told me that I have a tooth problem." (P3) "I did physiotherapy for several months; the doctor told me that you have cervical radiculopathy." (P19).

Subtheme 2.2: Life-Threatening Errors

• In some cases, misinterpretation of symptoms led to invasive and anxiety-provoking investigations:
  "I did CT and conventional angiography; they suspected cardiac problems." (P11).
• These experiences intensified fear and reinforced perceptions of bodily vulnerability.
• Subtheme 2.3: Chronic Mislabeling: Long-term misdiagnosis resulted in prolonged exposure to ineffective treatments:
• "For the last five years, I have been taking medication for migraine; I did not know I have nTOS." (P22)
• Participants described frustration at years of symptom management without etiological understanding.

Theme 3: Social and Familial Invalidation

Beyond medical encounters, participants reported invalidation within social and familial contexts, often leading to isolation and stigmatization.

Subtheme 3.1: Medical Gaslighting

Several participants perceived dismissal of their symptoms as psychological or fabricated:

"Even I faced social problems; they told me you have no disease, you are a psychopath all those investigations are normal, so you have no disease." (P5).

Such experiences contributed to erosion of trust in healthcare providers.

Subtheme 3.2: Familial Pressure

Family members, influenced by medical uncertainty, frequently encouraged psychiatric consultations:

• "Several times I visited psychiatrist; my family forced me to visit them. I knew that I have a somatic problem." (P17).
• This dynamic amplified patients’ sense of not being believed.

Theme 4: Profound Emotional Suffering

• The cumulative effect of diagnostic delay, mislabeling, and invalidation resulted in marked emotional distress.
• Subtheme 4.1: Isolation and Despair
• Participants expressed persistent feelings of loneliness, hopelessness, and emotional exhaustion:
• "I have been very upset as no one understands my suffering." (P9).
• Themes of hopelessness and emotional despair were identified in 84% of transcripts, underscoring the psychological toll of prolonged diagnostic uncertainty.

To facilitate interpretation, a conceptual model was developed to visually represent the cumulative and distressing diagnostic journey experienced by participants (Figure 1), integrating clinical, emotional, and social dimensions of the illness trajectory.

Discussion

Neurogenic TOS acts as a "diagnostic chameleon," with symptoms mimicking many common conditions. It presents a significant diagnostic challenge because its symptoms overlap extensively with a wide range of neurological, musculoskeletal, and systemic conditions, making differential diagnosis complex. Cervical spine pathology, particularly cervical radiculopathy due to disc herniation, spondylosis, or foraminal stenosis, is one of the most important differentials, as it can produce neck pain radiating to the upper limb, paresthesia, weakness, and sensory disturbances that mimic nTOS. Peripheral nerve entrapment syndromes such as carpal tunnel syndrome (median nerve), cubital tunnel syndrome (ulnar nerve), and radial tunnel syndrome may coexist with or masquerade as nTOS [6,7].

Brachial plexopathies due to trauma, tumors, radiation injury, or inflammatory processes must also be considered, particularly when symptoms are progressive, asymmetric, or associated with objective neurological deficits. In addition, Shoulder pathologies – such as rotator cuff disease, adhesive capsulitis, and impingement syndrome, commonly present with pain exacerbated by arm elevation and are frequently misinterpreted as thoracic outlet pathology. Myofascial pain syndromes, especially involving the scalene, trapezius, or pectoralis minor muscles, can closely mimic nTOS, contributing to pain, heaviness, and paresthesia without clear structural compression. Rheumatological conditions such as fibromyalgia, inflammatory arthritis, or connective tissue diseases may produce widespread pain, fatigue, and sensory symptoms [6,7].

Given this broad differential, the diagnosis of nTOS remains largely clinical, dependent on meticulous history-taking, thorough physical examination, exclusion of alternative diagnoses, and a multidisciplinary approach to avoid misdiagnosis and prolonged patient suffering [8,9].

Misdiagnosis in nTOS is not benign. In the present cohort, incorrect diagnostic attribution resulted in iatrogenic harm, including unnecessary dental extractions and invasive investigations such as conventional angiography. These findings underscore how diagnostic uncertainty can escalate into physical harm, psychological distress, and avoidable healthcare expenditures an issue increasingly recognized in patient safety literature.

Beyond biomedical consequences, participants described profound social invalidation in chronic illness contexts embodies the stigma of "invisible illnesses," where the absence of visible markers or abnormal test results often leads healthcare providers and society to attribute symptoms to psychosomatic causes, thereby undermining patient credibility and autonomy. This medical invalidation involves dismissal or minimization of patient reports, particularly among women, or young adults (typically nTOS patients), fostering a cycle of doubt that erodes patient agency. Medical invalidation often manifests as minimization or dismissal of patient-reported symptoms, particularly when diagnostic tests are normal. Rather than resolving uncertainty, normal results may paradoxically intensify clinician skepticism, shifting explanatory frameworks from physiological to psychological domains. This process can lead to diagnostic overshadowing, patient self-doubt, and erosion of trust in healthcare relationships [10,11]. The emotional suffering described by participants closely parallels Joseph Dumit's concept of "illnesses you have to fight to get treated," drawn from analyses of multiple chemical sensitivity (MCS), where patients face systemic barriers in uncertain, emergent illnesses, with bureaucratic and institutional reliance on established biomarkers denying legitimacy and forcing collective advocacy to counter exclusions. This fight manifests in newsgroup archives and patient activism, revealing rhetorical tactics by institutions that exploit scientific open-endedness to reject emerging facts, perpetuating costly struggles for recognition. Invalidation extends beyond clinics to social services and workplaces, with high discounting reported in insurance interactions, hindering return-to-work efforts and amplifying shame, while gender and minority intersections intensify stigma through diagnostic overshadowing leading to loneliness, helplessness, and mental health crises [10-13].

Clinical implications for managing nTOS emphasize rigorous training on key red flags to facilitate early detection and intervention, including positional symptoms such as pain, paresthesia, or weakness exacerbated by overhead arm positions, overhead activities, or specific postures like carrying heavy loads, alongside provocative tests like the elevated arm stress test (EAST). Other critical red flags encompass supraclavicular tenderness, thenar atrophy signaling chronic median nerve involvement, positive Adson or Wright maneuvers eliciting radial pulse diminution or symptom reproduction, and vascular signs like hand pallor or Raynaud-like phenomena during maneuvers. Multidisciplinary TOS clinics, integrating vascular surgeons, neurologists, physiatrists, physical therapists, and pain specialists, may cut diagnostic and treatment delays significantly potentially by streamlining evaluations via coordinated imaging (MRI neurography, dynamic venography), standardized protocols, and surgical referrals addressing the typical 1-2 year lag from symptom onset to definitive care that perpetuates deconditioning, psychological distress, and suboptimal outcomes in this anatomically complex syndrome involving scalene hypertrophy, cervical ribs, or fibromuscular bands. Evidence supports such clinics reducing misdiagnoses (e.g., labeling nTOS as "psychosomatic" or shoulder pathology), improving surgical success rates to 80-90% via first-rib resection or scalenectomy when conservative measures like physical therapy, nerve blocks, or Botox fail, and enhancing patient-centered metrics including return-to-work timelines and quality-of-life scores through holistic management that tackles myofascial triggers, posture correction, and psychosocial support. Implementing these in high-volume centers could standardize care, lower healthcare costs from repeated consultations [14-18]. 

Future directions in nTOS research prioritize mixed-methods studies incorporating male patients to address current gender imbalances, as existing literature predominantly features female cohorts due to higher reported prevalence and referral biases, potentially overlooking male-specific biomechanics like broader clavicular spans, occupational overhead strain in trades, or delayed presentations from stoicism, thereby enabling qualitative insights into lived experiences alongside quantitative metrics on symptom trajectories, diagnostic timelines, and treatment responses to refine inclusive diagnostic algorithms and prognostic models. Such studies could employ patient diaries, focus groups, and wearable sensor data to capture nuanced positional triggers absent in traditional cohorts, while longitudinal tracking via standardized scales (e.g., DASH for disability, SF-36 for quality-of-life) elucidates sex-disaggregated outcomes post-scalenectomy or therapy, informing tailored rehabilitation protocols that mitigate male underdiagnosis risks like conflation with rotator cuff pathology. Concurrently, intervention trials targeting clinician education represent a critical frontier, testing structured curricula to enhance recognition of red flags like supraclavicular tenderness or thenar wasting, countering few years diagnostic odyssey driven by misattribution to psychogenic causes. Randomized controlled trials could randomize primary care providers or neurologists to intervention arms versus controls, measuring endpoints like referral accuracy to multidisciplinary TOS clinics, reduction in unnecessary MRIs, and patient-reported delays, with embedded knowledge translation via pre/post assessments and fidelity checks to ensure scalability across community and academic settings [14,16-18].

This study has several limitations. The female-only sample limits generalizability to male populations. Retrospective accounts are subject to recall bias, and recruitment from a single specialty clinic may introduce selection bias. Nonetheless, the depth and consistency of narratives provide valuable insight into the lived experience of diagnostic delay in nTOS.

Conclusion

Delayed or missed diagnosis of nTOS inflicts multilayered suffering, extending beyond physical symptoms to encompass emotional distress, social invalidation, and erosion of trust in healthcare systems. The findings underscore the urgent need for a shift toward syndrome-aware, patient-centered, and empathetic diagnostic approaches that recognize both the clinical complexity of nTOS and the lived experiences of affected individuals. Early validation of patient narratives combined with rigorous clinical assessment and multidisciplinary collaboration has the potential to shorten diagnostic pathways, reduce iatrogenic harm, and transform prolonged diagnostic odysseys into meaningful trajectories of recognition, relief, and recovery.

Declarations

Conflicts of interest: The authors have no conflicts of interest to disclose.

Ethical approval: Not applicable.

Patient consent (participation and publication): Written informed consent was obtained from all patients and/or their legal guardians for participation in this study and for the publication of any accompanying images, clinical information, and other data included in the manuscript.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: SHM and BAA were major contributors to the conception of the study, as well as to the literature search for related studies. FHK, YNA and AKG were involved in the literature review and the writing of the manuscript. SKA, NSS, LJM, ASH, CSO, AHA, OMH, LAS, AAM, and AHH were involved in the literature review, the design of the study, the critical revision of the manuscript, and the preparation of the table and figure.  FHK and BAA confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Use of AI: ChatGPT Plus (OpenAI, version 4) was used solely to assist with language editing and to improve the clarity of the manuscript. All content was carefully reviewed and verified by the authors, who take full responsibility for the accuracy, integrity, and originality of the entire work.

Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abstract

Background

Neurogenic thoracic outlet syndrome (nTOS) is the most prevalent subtype of thoracic outlet syndrome and remains one of the most controversial conditions in peripheral nerve and thoracic disorders. Despite widespread recognition of conservative therapy as initial management, substantial variation exists across medical specialties regarding diagnosis, duration of nonoperative treatment, and indications for surgery. These discrepancies suggest underlying differences in how nTOS is conceptualized rather than disagreement over available treatment options.

Objectives
This study aimed to explore and compare the perspectives of different medical specialties on the management of confirmed nTOS, with particular attention to conservative therapy, surgical indications, and underlying explanatory models.

Methods

A qualitative descriptive study was conducted using semi-structured interviews with 40 physicians from five specialties involved in nTOS care: thoracic and vascular surgery, neurosurgery, orthopedic surgery, neurology, and rheumatology (eight participants per specialty). Participants were recruited using purposive sampling based on clinical experience with nTOS. All interviews centered on a standardized question addressing management strategies following confirmation of nTOS. Data were analyzed using reflexive thematic analysis.

Results

Five overarching themes emerged. All specialties endorsed physiotherapy as first-line treatment, though recommended duration varied widely. Profound disagreement existed regarding the role of surgery, ranging from early operative intervention to complete rejection. Surgeons tended to frame nTOS as a mechanical compression disorder, whereas neurologists and rheumatologists frequently expressed diagnostic skepticism and favored prolonged conservative management. Orthopedic surgeons adopted selective surgical strategies focused on musculoskeletal contributors. Across specialties, variability was driven primarily by differing conceptual models of nTOS rather than by technical considerations.

Conclusion

Management variability in nTOS arises chiefly from divergent understandings of the condition itself. Without addressing these foundational differences, inconsistency in care is likely to persist. Interdisciplinary consensus-building that integrates anatomical, neurological, and pain-based frameworks is essential for developing coherent, patient-centered management pathways for nTOS.

Introduction

Neurogenic thoracic outlet syndrome (nTOS) is the most common and arguably the most controversial subtype of thoracic outlet syndrome (TOS), accounting for more than 90% of reported cases. It is characterized by compression of the brachial plexus as it traverses the thoracic outlet, leading to a constellation of symptoms including neck and shoulder pain, upper limb paresthesia, weakness, fatigue, and functional impairment. Despite its relatively high prevalence compared with vascular forms of TOS, nTOS remains poorly understood, frequently underdiagnosed, and inconsistently managed across medical specialties [1-3].

Management of nTOS is contentious. Conservative treatment, including physiotherapy, postural correction, pain management, and behavioral modification, is generally recommended as first-line therapy. However, the indications for surgical intervention, optimal timing, patient selection, and preferred surgical approach remain subjects of ongoing debate. Surgical decompression most commonly involving first rib resection and scalenectomy has been reported to yield favorable outcomes in selected patients, yet reported success rates vary widely, and complications are not negligible. These uncertainties contribute to divergent management philosophies across specialties involved in nTOS care [4-7].

The multidisciplinary nature of nTOS care further complicates consensus. Thoracic and vascular surgeons often approach nTOS from an anatomical and decompressive perspective, emphasizing surgical solutions in carefully selected patients. Neurosurgeons may focus on neural pathology, central sensitization, and differential diagnoses involving cervical spine or peripheral nerve disorders. Orthopedic surgeons frequently view symptoms through the lens of musculoskeletal dysfunction, shoulder pathology, or cervical spine disease. Neurologists may prioritize electrodiagnostic findings and are often skeptical of nTOS in the absence of objective abnormalities. Rheumatologists, meanwhile, may encounter patients with overlapping pain syndromes or inflammatory conditions, influencing their perception of nTOS as a diagnosis of exclusion. These differing conceptual frameworks shape not only clinical decision-making but also attitudes toward diagnosis, referral, and treatment [8-11].

While numerous quantitative studies have evaluated surgical outcomes, diagnostic tests, and rehabilitation protocols in nTOS, relatively little attention has been paid to the perspectives of clinicians themselves. Understanding how different specialties conceptualize nTOS, interpret evidence, and justify their management strategies is critical, as these views directly influence patient pathways, interdisciplinary collaboration, and ultimately clinical outcomes. Qualitative research is particularly well suited to exploring such complex, context-dependent phenomena, allowing for in-depth examination of beliefs, experiences, uncertainties, and professional cultures that cannot be adequately captured through quantitative methods alone [12].

Therefore, this qualitative study aims to explore and compare the views of different specialties (thoracic and vascular surgeons, neurosurgeons, orthopedic surgeons, neurologists, and rheumatologists) regarding the management of nTOS. By elucidating areas of consensus, disagreement, and uncertainty across specialties, this research seeks to inform more coherent multidisciplinary approaches, identify barriers to collaboration, and contribute to the development of more patient-centered and evidence-informed care pathways for individuals with nTOS.

Methods

Study design

This study adopted a qualitative descriptive design to explore how different medical specialties manage confirmed cases of nTOS. Given the complexity, controversy, and specialty-dependent interpretations surrounding nTOS, a qualitative approach was chosen to capture clinicians’ reasoning, preferences, and professional perspectives that cannot be adequately quantified.

Participants and sampling

Physicians from five specialties commonly involved in the care of nTOS were included: thoracic and vascular surgery, neurosurgery, orthopedic surgery, neurology, and rheumatology. Participants were recruited using purposive sampling based on their direct clinical experience with patients diagnosed with nTOS.

A total of 40 clinicians participated in the study. Each specialty was represented by eight participants, ensuring sufficient diversity of viewpoints within and across specialties. Participants varied in years of experience and practice settings, enhancing the richness of the data.

Data collection

Data were collected through semi-structured interviews. All participants were asked a single core, standardized question to ensure comparability across specialties:

“If you confirm that a patient has neurogenic thoracic outlet syndrome, how do you manage this patient?”

Follow-up prompts were used when needed to clarify responses, particularly regarding duration of conservative therapy, indications for surgery, and preferred surgical approaches. Interviews were conducted in person or online, recorded with consent, and transcribed verbatim for analysis.

Data analysis

Data were analyzed using reflexive thematic analysis as described by Braun and Clarke [12]. Analysis proceeded through the following phases:

1. Familiarization with the data through repeated reading of transcripts
2. Generation of initial codes reflecting management strategies, attitudes toward surgery, and specialty-specific reasoning
3. Development of preliminary themes across and within specialties
4. Review and refinement of themes to ensure internal coherence and clear distinction
5. Definition and naming of final themes

Analysis was conducted iteratively, with reflexive attention to how professional background and clinical culture shaped interpretations. Discrepancies and contradictions were treated as meaningful data rather than inconsistencies.

Ethical considerations

Participation was voluntary, and informed consent was obtained from all participants. All data were anonymized to protect participant identity. The study involved clinicians only and did not include patient data.

Results

Analysis revealed marked variation in the management of nTOS across specialties, particularly regarding the role of surgery, duration of conservative treatment, and confidence in the diagnosis itself. Five overarching themes emerged.

Theme 1: Universal Endorsement of Physiotherapy as First-Line Treatment

Across all specialties, physiotherapy was consistently identified as the initial management strategy for confirmed nTOS. However, the recommended duration varied substantially, ranging from two weeks to six months.

• Thoracic and vascular surgeons most commonly recommended 1–3 months of physiotherapy.
• Orthopedic surgeons and neurologists often advocated prolonged physiotherapy (up to six months).
• Rheumatologists generally supported physiotherapy as the primary or sole treatment.

This variation reflects differing thresholds for declaring conservative treatment failure.

Theme 2: Profound Disagreement Regarding the Role of Surgery

Opinions on surgical intervention ranged from early and decisive to complete rejection.

Thoracic and Vascular Surgeons:

This group demonstrated the widest internal variability:

• Some favored early surgery, even direct operative intervention after short physiotherapy trials.
• Others recommended surgery only after structured conservative management.
• A minority rejected surgery entirely, citing poor outcomes and limited benefits.

Preferred surgical approaches included supraclavicular, transaxillary, and minimally invasive video assisted thoracic surgery/robotic assisted thoracic surgery-VATS/RATS) first rib resection, often tailored to venous involvement or pectoralis minor tenderness.

Neurosurgeons:

Neurosurgeons were divided:

• Some viewed nTOS as a clear anatomical compression requiring surgery.
• Others avoided intervention entirely, preferring referral to vascular surgeons.
• Posterior approaches were rarely mentioned and limited to individual preferences.

Theme 3: Selective and Limited Surgical Indications Among Orthopedic Surgeons

Orthopedic surgeons generally adopted a conservative and selective surgical philosophy:

• Surgery was reserved for chronic cases, documented anatomical abnormalities, or failure of extended physiotherapy.
• Several rejected first rib resection, favoring isolated scalenectomy or pectoralis minor tenotomy.
• A minority supported direct surgical referral to vascular surgeons.

This reflects the musculoskeletal framing of nTOS symptoms.

Theme 4: Skepticism and Diagnostic Reframing by Neurologists

Neurologists frequently expressed diagnostic skepticism even when they are asked regarding the management of nTOS:

• Several participants attributed symptoms to migraine, central sensitization, or non-structural causes.
• Surgery was considered only in cases with objective findings, such as muscle atrophy.
• Most recommended prolonged conservative therapy, with surgical referral as a last resort.

This group demonstrated the highest threshold for surgical acceptance.

Theme 5: nTOS as a Diagnosis of Exclusion Among Rheumatologists

Rheumatologists often conceptualized nTOS as a diagnosis of exclusion:

• Most endorsed physiotherapy initially.
• Surgical referrals were deferred to vascular surgeons and often viewed with skepticism.
• Some explicitly stated that surgery is ineffective or unnecessary.

This perspective reflects overlap with chronic pain syndromes and inflammatory conditions (Table 1).

Discussion

The study illustrates that variability in the management of nTOS is driven less by disagreement over treatment modalities and more by fundamentally different ways in which clinicians understand the condition itself rather than reflecting simple differences in training, the observed diversity in management strategies appears rooted in contrasting explanatory models of nTOS, ranging from structural compression to functional or centrally mediated pain syndromes. Similar conceptual fragmentation has been repeatedly identified as a central challenge in advancing care for nTOS [13–15].

Although conservative management was universally endorsed, the absence of shared criteria for adequacy or failure of nonoperative therapy emerged as a critical fault line between specialties. The wide range of physiotherapy durations recommended by participants suggests conservative treatment functions as both therapy and diagnostic test, with clinicians using response to rehabilitation to validate or refute the diagnosis. This implicit diagnostic role of physiotherapy has been noted in previous studies and may partly explain why treatment pathways diverge early in the disease course [16,17]. Importantly, prolonged conservative management may delay surgical referral in patients who could potentially benefit from decompression, while premature escalation risks unnecessary intervention.

Disagreement surrounding surgery reflects ongoing uncertainty regarding the pathophysiology of nTOS rather than technical differences in operative approach. Surgeons who favored intervention generally conceptualized nTOS as a mechanical compression disorder, whereas those opposing surgery questioned the causal relationship between anatomical findings and symptoms. This division mirrors inconsistencies in the literature, where anatomical abnormalities are common in asymptomatic individuals and clinical improvement does not always correlate with radiological or intraoperative findings [1,11,18,19]. Consequently, surgical decision-making remains heavily dependent on clinician judgment rather than objective thresholds.

Specialty-specific skepticism, particularly among neurologists and rheumatologists, highlights the tension between symptom-based diagnoses and disciplines that prioritize objective biomarkers. Neurogenic TOS challenges traditional diagnostic paradigms because standard electrodiagnostic studies are often normal and imaging findings are nonspecific [20,21]. From a neurological or rheumatological standpoint, this diagnostic ambiguity fosters reinterpretation of symptoms as functional, inflammatory, or centrally mediated disorders. While such caution is justifiable, it may inadvertently marginalize patients whose symptoms do arise from peripheral neural compression.

The selective surgical stance adopted by many orthopedic surgeons reflects a musculoskeletal framing of nTOS, emphasizing regional biomechanics over thoracic outlet anatomy. This perspective aligns with growing interest in pectoralis minor syndrome and isolated scalene pathology as contributors to upper limb symptoms [22,23]. However, the lack of consensus on whether these entities represent distinct conditions or part of the nTOS spectrum further complicates interdisciplinary communication and treatment planning.

A notable implication of these findings is that nTOS lacks a shared “clinical ownership.” Instead, responsibility is frequently transferred between specialties, resulting in circular referrals and inconsistent care pathways. Similar patterns have been described in other contested pain syndromes and are known to contribute to patient dissatisfaction and healthcare inefficiency [24,25]. Multidisciplinary evaluation has been proposed as a solution, but without alignment at the conceptual level, such models risk becoming parallel rather than integrative.

There are limitations to this study; The study reflects clinicians stated practices rather than observed behavior, and responses may have been influenced by recall or professional positioning. Additionally, perspectives may vary across healthcare systems. Nevertheless, the consistency of themes across specialties suggests that the findings capture widely held views rather than isolated opinions.

Implications for Practice and Research

Future efforts should focus on developing interdisciplinary definitions of conservative treatment failure, clearer indications for surgical referral, and shared diagnostic language. Consensus statements that integrate anatomical, neurological, and pain-based frameworks may help bridge existing divides. Further qualitative work involving patients may also clarify how professional disagreement translates into lived experience.

Conclusion

This study demonstrates that disagreement in nTOS management arises primarily from divergent conceptualizations of the condition rather than lack of therapeutic options. Without addressing these underlying differences, variability in care is likely to persist. Meaningful progress in nTOS management will depend on sustained interdisciplinary engagement aimed at reconciling competing models into coherent, patient-centered care pathways.

Declarations

Conflicts of interest: The authors have no conflicts of interest to disclose.

Ethical approval: Not applicable.

Patient consent (participation and publication): Not applicable.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: SHM and BAA were major contributors to the conception of the study, as well as to the literature search for related studies. FHK, SKA and AKG were involved in the literature review and the writing of the manuscript. ASH, LAS, HSN, RHA, ZOKA, SSR, SOA, NSS, CSO, LJM, and YKI were involved in the literature review, the design of the study, the critical revision of the manuscript, and the processing of the table.  FHK and BAA confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Use of AI: ChatGPT Plus (OpenAI, version 4) was used solely to assist with language editing and to improve the clarity of the manuscript. All content was carefully reviewed and verified by the authors, who take full responsibility for the accuracy, integrity, and originality of the entire work.

Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.