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.

Qualitative research works at revealing the depth of human experiences, cultural nuances, and complex social dynamics, yet it confronts formidable challenges including pervasive researcher subjectivity, methodological inconsistencies, ethical intricacies, resource burdens, data management overload, and struggles with establishing rigor and transferability that often invite skepticism from quantitative paradigms. These obstacles not only complicate the research process but also threaten the perceived validity and broader applicability of findings in fields like health, education, and social sciences. Addressing them requires deliberate strategies to fortify qualitative inquiry's contributions to knowledge [1].

Subjectivity and Researcher Bias

The interpretive essence of qualitative research inherently invites researcher bias, as personal worldviews, cultural backgrounds, and preconceptions influence every stage from question formulation to data interpretation. For example, during thematic analysis of interviews, a researcher's emphasis on certain participant quotes might overlook contradictory evidence, leading to unbalanced narratives. Mitigation strategies like reflexivity where researchers explicitly document their influences and triangulation, cross-verifying data from multiple sources, prove essential, though full elimination of subjectivity remains impractical in this paradigm [2].

Methodological Design and Rigor Hurdles

Crafting a robust qualitative design demands precise alignment between philosophical underpinnings, research questions, and methods such as phenomenology, grounded theory, or discourse analysis, yet mismatches frequently occur due to insufficient expertise. Determining data saturation when new data yields no fresh insights relies on subjective judgment, complicating claims of completeness, while ensuring transferability to other contexts necessitates detailed "thick descriptions" of participants and settings. In health research, these issues amplify without clear audit trails, prompting calls for standardized rigor criteria akin to quantitative benchmarks [3].

Data Collection and Management Complexities

Gathering qualitative data through prolonged interviews, focus groups, or ethnographies generates vast, unstructured volumes of transcripts, field notes, and multimedia that overwhelm storage, organization, and preliminary sorting. Logistical barriers, like recruiting hard-to-reach participants or adapting to virtual formats, further delay progress, while ensuring consistency across sessions proves elusive without rigid protocols. Digital tools offer relief for transcription and initial coding, but they demand technical proficiency and risk diluting contextual richness if misapplied [1-4].

Analysis and Interpretation Demands

Transforming raw qualitative data into coherent themes involves iterative coding, pattern identification, and narrative synthesis, a labor-intensive process prone to interpretive drift among team members. Balancing depth with transparency challenges researchers, especially when handling ambiguous or contradictory data, and emerging AI aids accelerate this but introduce concerns over algorithmic bias eroding human insight. Peer debriefing, inter-coder reliability checks, and software like NVivo enhance trustworthiness, yet the time investment often months strains projects and underscores the need for advanced training [4].

Ethical, Practical, and Interdisciplinary Tensions

Ethical navigation intensifies in qualitative work due to intimate participant interactions, raising issues like securing ongoing consent, safeguarding anonymity in sensitive topics, and managing power imbalances with vulnerable groups. Practical constraints, including high costs for fieldwork and participant fatigue, compound these, while interdisciplinary skepticism particularly from STEM fields questions replicability and generalizability. Mixed-methods integration and decolonial approaches that center marginalized voices offer bridges, but they require institutional support and evolved review board processes [5].

Emerging Trends and Solutions

Technological innovations like AI-driven analysis and big data integration promise efficiency, yet they challenge traditional methodological purity and amplify ethical risks around data privacy. Postqualitative and indigenous methodologies push boundaries by rejecting linear processes, fostering inclusivity amid globalization. Researchers advance by prioritizing comprehensive training, open-access protocols for auditability, and collaborative networks to elevate qualitative work's stature and impact.

Conflicts of interest: The author has no conflicts of interest to disclose.

Abstract

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease commonly affecting women of reproductive age. Its overlap with HELLP syndrome (Hemolysis, Elevated Liver Enzymes, and Low Platelet Count) and antiphospholipid syndrome (APS) during pregnancy is rare and presents diagnostic and therapeutic challenges due to shared clinical and laboratory features. This report describes a case of pre-existing SLE complicated by the concurrent occurrence of SLE flare, HELLP syndrome, and APS during pregnancy.

Case presentation

A 26-year-old female with known SLE presented with right upper quadrant abdominal pain and hypertension two days following a mid-trimester abortion at 22 weeks of gestation. Laboratory evaluation revealed thrombocytopenia, elevated liver enzymes, and hemolysis, consistent with HELLP syndrome. The presence of lupus anticoagulant and anticardiolipin antibodies, in conjunction with her obstetric history, supported the diagnosis of APS. The patient was treated with high-dose corticosteroids and anticoagulation, resulting in significant clinical improvement.

Literature review

A review of literature highlights the consistent presentation of nonspecific symptoms such as abdominal pain, nausea, and hypertension in patients with overlapping SLE, HELLP syndrome, and APS. Laboratory findings often reveal thrombocytopenia, elevated liver enzymes, and hemolysis, reflective of underlying microangiopathic processes. Therapeutic strategies typically involve corticosteroids and anticoagulation, with plasmapheresis reserved for severe cases.

Conclusion

The coexistence of SLE flare, HELLP syndrome, and APS during pregnancy is a rare and complex condition that requires careful evaluation. Early recognition and appropriate management are crucial for achieving favorable outcomes.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement, affecting approximately 20 to 150 per 100,000 individuals worldwide, with a strong female predominance [1,2]. It commonly presents with fatigue, arthralgia, skin manifestations, and renal or hematological complications, but its presentation can vary widely depending on disease activity [3]. Pregnancy in patients with SLE is considered high-risk due to increased risks of preeclampsia, fetal loss, and preterm delivery [4]. Antiphospholipid syndrome (APS) is another autoimmune disorder that frequently overlaps with SLE. It is characterized by the presence of antiphospholipid antibodies and is associated with thrombotic events and pregnancy complications such as recurrent miscarriage and intrauterine growth restriction [5,6]. HELLP (Hemolysis, Elevated Liver Enzymes, and Low Platelet Count) syndrome is a severe form of preeclampsia that can develop in up to 0.9% of pregnancies, usually leading to hepatic dysfunction, hypertension, and coagulopathy [7]. These conditions exhibit overlapping clinical and laboratory features such as thrombocytopenia, elevated liver enzymes, and hemolysis, making diagnosis and management particularly challenging [3-7].

This report presents a known case of SLE with the simultaneous occurrence of SLE flare, HELLP syndrome, and APS during pregnancy. The report was prepared in accordance with the CaReL guidelines, with all references evaluated for reliability and scientific integrity [8,9].

Case Presentation

Patient information

A 26-year-old woman presented with a one-week history of right upper quadrant abdominal pain. She had a second-trimester abortion at 22 weeks of gestation, delivered vaginally two days earlier. Her medical history included SLE, diagnosed eight years earlier following a miscarriage. Because of recurrent abortions, she was placed on aspirin during pregnancy. She also had a history of gestational hypertension.

Clinical findings

Examination revealed significant tenderness in the epigastric region upon light palpation, with no changes in mental status.

Diagnostic approach

Laboratory investigations revealed markedly elevated liver enzymes, including alanine aminotransferase (ALT: 2500 U/L; reference: 7–56 U/L) and aspartate aminotransferase (AST: 3000 U/L; reference: 10–40 U/L). She also had thrombocytopenia, with a platelet count of 50,000/mm³ (reference: 150,000–450,000/mm³), and a prolonged prothrombin time (PT) of 22 seconds (reference: 11–15 seconds) with an elevated international normalized ratio (INR: 2.0; reference: 0.8–1.2). D-dimer levels were markedly elevated at 2500 ng/mL (reference: <500 ng/mL), while fibrinogen was decreased to 50 mg/dL (reference: 200–400 mg/dL). Peripheral blood smear demonstrated schistocytes, indicative of ongoing microangiopathy. Autoimmune testing confirmed active SLE, with a positive antinuclear antibody (ANA) and elevated anti-double-stranded DNA (anti-dsDNA) titers. Imaging studies, including an abdominal computed tomography scan, demonstrated severe hepatic necrosis without evidence of rupture or hematoma. These findings confirmed the coexistence of SLE flare, HELLP syndrome, and APS, a rare and complex presentation.

Therapeutic intervention and follow-up

The patient was admitted to the intensive care unit for supportive care and initiated methylprednisolone pulse therapy for three consecutive days, resulting in significant improvement. Liver enzymes normalized, platelet counts increased, and symptoms resolved. Anticoagulation with warfarin was started for APS, and hydroxychloroquine was continued for SLE management. At discharge, she was stable and referred to rheumatology for long-term follow-up.

Discussion

Pregnancy in patients with SLE carries an increased risk of adverse maternal and fetal outcomes, including preeclampsia, fetal loss, and preterm birth, particularly in cases complicated by active disease [5]. The presence of APS, a thrombotic disorder defined by antiphospholipid antibodies, further increases pregnancy risks by promoting thrombosis, recurrent miscarriages, and placental insufficiency [6].

HELLP syndrome, a severe form of preeclampsia, presents with hepatic dysfunction, endothelial injury, and hematologic abnormalities, leading to substantial maternal and fetal morbidity [7].

The present case developed HELLP syndrome and APS following a mid-trimester abortion at 22 weeks, reflecting the complex interplay of these conditions and the challenges in diagnosis and management. A brief literature review identified 4 reported cases of concurrent (SLE and APS), (SLE and HELLP syndrome), or (APS and HELLP syndrome). All occurred in young women aged 26–39 years, underscoring the well-established female predominance of these conditions (Table 1) [3-7].

Pregnancy is a known trigger for SLE flares, and the additional presence of APS further increases the risk of obstetric complications [2,4,5]. The present case is consistent with these observations, as the patient’s history of SLE and pregnancy loss conferred an elevated risk for the development of APS and HELLP syndrome.

The most common symptoms reported in the reviewed cases were right upper quadrant abdominal pain, hypertension, nausea, and dyspnea, which are classic signs of HELLP syndrome [3-7]. Sakhel et al. reported tachypnea and dyspnea, which can indicate pulmonary involvement or preeclampsia-related respiratory distress [7]. Osmanagaoglu et al. reported another case presenting with synovitis, butterfly rash, and confusion, indicative of either neurological lupus involvement or eclampsia [4]. Some cases presented with vision disturbances and chest discomfort, which may indicate APS-related microvascular thrombotic events [5]. While some patients had neurological involvement, the present case exhibited a severe hypertensive episode, reinforcing the complexity of these overlapping conditions.

Laboratory investigations across cases demonstrated consistent hematologic abnormalities, including thrombocytopenia, elevated liver enzymes, and hemolysis, which are defining features of HELLP syndrome [3]. One case reported proteinuria, which is more suggestive of SLE nephritis or preeclampsia-related renal dysfunction [4]. In another case, hemolysis was confirmed through microangiopathic findings rather than an immune-mediated mechanism [6]. Patients with APS frequently exhibited prolonged PT/INR, elevated D-dimer levels, and thrombocytopenia, reflecting the hypercoagulable state of APS [5].

The present case demonstrated severe thrombocytopenia, elevated ALT/AST, and hemolysis, with positive lupus anticoagulant and anticardiolipin antibodies confirming APS and elevated anti-dsDNA titers indicating active SLE. This profile closely mirrors the reviewed cases of the literature, emphasizing the diagnostic overlap between HELLP syndrome, SLE flares, and APS.

Although imaging findings were not reported in all cases, hepatic involvement was a significant feature in those with severe HELLP syndrome or APS-associated thrombosis. Osmanagaoglu et al. reported a case of hepatic infarctions and subcapsular hematomas, suggesting vascular damage secondary to HELLP syndrome or APS-related thrombosis [7]. Veres et al. described another case with hepatic microangiopathic changes in the absence of infarction, highlighting the diverse spectrum of hepatic involvement in such patients [5]. The present case exhibited hepatic involvement in imaging, consistent with hepatic dysfunction in severe HELLP syndrome, reinforcing the value of imaging studies in distinguishing these conditions.

Management strategies varied depending on the severity of the disease, but high-dose corticosteroids were universally used to suppress SLE flares and reduce systemic inflammation [6]. APS patients received anticoagulation therapy with heparin or warfarin to prevent thrombotic complications. In severe cases, plasmapheresis and intravenous immunoglobulin were administered to manage catastrophic APS or refractory hemolysis [5]. The case reported by Osmanagaoglu et al. required therapeutic abortion due to the severity of maternal complications, highlighting the need for individualized obstetric decision-making in these high-risk pregnancies [4].

The present case was treated with methylprednisolone for SLE flare and heparin for APS, resulting in significant clinical improvement, which mirrors the treatment success observed in the reviewed cases (Table 1).

Outcomes among reported cases varied based on disease severity and timing of intervention. While most patients responded well to treatment, the case reported by Osmanagaoglu et al. resulted in maternal mortality, particularly due to multi-organ failure and delayed diagnosis [4]. Other cases reported full recovery following corticosteroid therapy and anticoagulation [5,6]. The case reported by Appenzeller et al. demonstrated partial resolution of symptoms but continued to require long-term monitoring due to APS-related complications [3].

Early intervention played a crucial role in improving prognosis, as seen in cases that received timely corticosteroid and anticoagulation therapy. The present case, diagnosed early and treated promptly, achieved clinical stabilization, underscoring the critical role of timely diagnosis and multidisciplinary management in improving maternal outcomes.

Conclusion

The coexistence of SLE flare, HELLP syndrome, and APS during pregnancy is a rare and complex condition that requires careful evaluation. Early recognition and appropriate management are crucial for achieving favorable outcomes.

Declarations

Conflicts of interest: The authors declare no conflicts of interest.

Ethical approval: Not applicable.

Patient consent (participation and publication): Written informed consent was obtained from the patient for participation and publication.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: SHS and RSA were significant contributors to the conception of the study and the literature search for related studies. KAN and HAN were involved in the literature review, study design, and manuscript writing.  DTG, NHA, HRA, HMM, JIH, and KFH were involved in the literature review, study design, critical revision of the manuscript, and table processing. RSA and HAN confirm the authenticity of all the raw data. All authors approved the final version of the manuscript.

Use of AI: ChatGPT-4 was used to assist in language editing and improving the clarity of the manuscript. All content was reviewed and verified by the authors. Authors are fully responsible for the entire content of their manuscript.

Data availability statement: Not applicable.

Abstract

Introduction

During pregnancy, women may develop blood glucose abnormalities like gestational diabetes mellitus (GDM) or, rarely, type 1 diabetes (T1D), which can lead to complications. Anti-GAD65 is a key antibody used in diagnosing T1D. This study presents a rare case of T1D developing a week before birth, with transient anti-GAD65 positivity.

Case presentation

A 38-year-old patient who delivered a baby a week earlier and had high blood glucose was admitted to the hospital with shortness of breath, chest tightness, abdominal pain, generalized weakness, nausea, and repeated vomiting. She had elevated anti-GAD65 and was diagnosed with T1D and diabetic ketoacidosis. Insulin injection was prescribed, with lifestyle modifications, later oral hypoglycemic medications added. After a few months, both anti-IA2 and anti-GAD65 antibodies were negative.

Literature review

Seven cases of T1D during or after pregnancy were reviewed. Six reported BMI. The mean HbA1c was >7.63%. Mean anti-GAD65 was 190.74 U/mL, two were borderline and one negative. Six had previously diagnosed GDM. Treatments varied, including insulin and dietary management. All infants were safely delivered, one miscarried in a subsequent pregnancy. Insulin resistance increases during pregnancy due to hormonal changes, raising the risk of GDM, T1D, and type 2 diabetes. Emerging postpartum, often indicated by anti-GAD65 antibodies, though levels can fluctuate. Cases show complications like preeclampsia, DKA, and miscarriage. Early detection, strict glucose control, and monitoring antibody patterns are critical for managing risks and improving maternal and fetal outcomes.

Conclusion

Blood glucose should be monitored during pregnancy, and anti-GAD65 may signal T1D, requiring appropriate management.

Introduction

Type 1 diabetes (T1D) is a condition characterized by a lack of the hormone insulin due to an autoimmune response that destroys the pancreas's insulin-producing β cells [1]. During pregnancy, women may develop an abnormal tolerance to glucose, which is not severe enough to be classified as overt diabetes mellitus, known as gestational diabetes mellitus (GDM). This condition increases the possibility of type 2 diabetes (T2D) after birth, and the risk of T1D, especially if they have autoantibodies targeting the beta cells of the pancreas [2]. Around 2-17% of expectant mothers empierce GDM. While glucose metabolism typically returns to normal after childbirth, there is a high chance, between 34% up to half of the cases, that it will recur in future pregnancies, with around 6% developing into T1D [3]. Throughout an asymptomatic period of variable length, different autoantibodies targeting islet cell autoantigens can be identified, and these play a key role in recognizing individuals at an increased risk of developing clinical disease. Glutamic acid decarboxylase (GAD) is a key enzyme, antibodies against said enzyme or anti-GAD65 are one of the primary antibodies associated with T1D, with two isoforms having molecular weights of 65 kDa and 67 kDa. This antibody is found in most individuals with preclinical or recently diagnosed T1D. [4]. It is well established that pregnancies that involve T1D face a greater risk of complications affecting the mother, fetus, and newborn compared to those with uncomplicated pregnancies [5]. Poorly managed high blood glucose during pregnancy can result in serious complications, including stillbirth, miscarriage, congenital disabilities, and pregnancy-related conditions like hypertension or preeclampsia [1]. The aim of this study is to show a rare case of T1D developing a week before giving birth, with a transient anti-GAD65 positive test result, and a literature review. The references used in this case report have been checked for reliability and compiled with CaReL guidelines [6,7].

Case Presentation

Patient information

A 38-year-old female was admitted to the hospital with shortness of breath, chest tightness, abdominal pain, generalized weakness, nausea, and repeated vomiting that had persisted for two days before admission. She had been pregnant and had delivered a stillborn baby one week earlier at 39 weeks of gestation.

Clinical findings

On clinical examination, the patient appeared distressed and exhibited tachypnoea. Her heart rate was 110 beats per minute, respiratory rate was 32 cycles per minute, blood pressure was 110/70 mmHg, and her temperature was 38°C. Her BMI was 34 kg/m². She had no history of chronic disease.

Diagnostic approach

The patient was admitted to the hospital, resuscitated, and diagnosed with diabetic ketoacidosis (DKA), based on the presence of ketone bodies in the urine (3+) and acidosis confirmed by arterial blood gas analysis (pH 7.16, bicarbonate 12 mmol/L), her blood glucose was over 300 mg/dL. Anti-GAD test came back elevated at (65.1 U/mL), leading to a diagnosis of T1D.

Therapeutic intervention

Several days before her scheduled Cesarean section, she was admitted to the hospital due to elevated blood pressure and blood glucose levels. She was treated with insulin therapy to manage her condition. Following the surgery, the patient was evaluated by an endocrinologist for her hyperglycemic condition. Based on her medical history, the decision was made to discontinue insulin therapy and initiate lifestyle modifications along with oral hypoglycemic medications. However, two days after this change in treatment, she developed DKA. To treat her DKA, she received intravenous insulin infusion and was rehydrated with normal saline and received potassium.

Follow-up

A few months after starting insulin therapy, she underwent testing for T1D-related autoantibodies, which came back within normal ranges. The results were negative for both anti-IA2 and anti-GAD65 antibodies.

Discussion

The sensitivity to insulin declines during pregnancy, primarily due to the influence of placental hormones. Human growth hormone, along with human placental lactogen, plays a key role in regulating maternal metabolism and supporting the growth of the fetus, with levels gradually increasing throughout the first and second trimesters. Pregnancy is also associated with a reduced secretion of human growth hormone in response to low blood glucose, which further contributes to the resistance toward insulin. These effects are compounded by hormonal changes involving progesterone, prolactin, cortisol, adiponectin, and leptin [1]. Seven cases of T1D arising during or after pregnancies have been reviewed (Table 1) [2, 3, 8-10]. Six cases mentioned the patient’s body mass index, one of them mentioning the pre-pregnancy body mass index. The mean HbA1c was over 7.63, only one case didn’t mention performing a HbA1c test. The mean anti-GAD65 was 190.74 U/mL, with two cases being borderline at around 2 U/mL and one negative at 0.268 U/mL. Six cases were associated with GDM before T1D. Different treatments and therapeutics were used, including insulin therapy and dietary managements. All the infant were delivered safely, but one case had another pregnancy a few months later and the fetus miscarried.

Pregnancies with T1D who have poor blood glucose control face a much higher risk of developing preeclampsia compared to those who do not. Even if T1D is not involved, higher blood glucose levels are consistently linked to increased birth weight and other complications during and after birth [5]. Ikeoka et al. report a case of a 27-year-old pregnant female diagnosed with T1D through a 75-g oral glucose tolerance test conducted during the postpartum monitoring of GDM, which itself was diagnosed earlier after previous plasma glucose measurements prompted a 75-g oral glucose tolerance test. She was advised to follow a nutritional treatment plan and delivered the infant. She had several follow-ups and was diagnosed with established diabetes. She was pregnant again after four months, and intensive insulin therapy was initiated, but sadly, she experienced a miscarriage of the second fetus one week later [2].

Another serious and potentially deadly condition that can result from T1D is DKA, resulting from a lack of insulin, which was also present in this case. High levels of ketones in the blood and elevated blood glucose, although the specific diagnostic criteria can vary. Symptoms typically develop over a few hours and include vomiting, nausea, intense thirst, and frequent urination [11]. Around 1–2% of pregnancies that have glucose tolerance impairment develop DKA. It most commonly affects pregnancies with T1D, but it can also occur, though less frequently, in those with T2D, newly diagnosed T1D, or GDM [9]. Education on diabetes self-management, along with medical and psychological support, can play an essential role in preventing and managing DKA [11]. Himuro et al. report a case of a patient who, although she had normal glucose tolerance in the first trimester, was diagnosed with T1D and went on to develop DKA in her late pregnancy period. The patient was promptly treated with saline and intensive insulin therapy. Following this treatment, her blood glucose levels returned to normal [9].

About 5-10% of all individuals with diabetes have T1D. The autoimmune response is marked by the presence of autoantibodies targeting insulin, tyrosine phosphatase enzyme IA-2, glutamic acid decarboxylase 65, and islet cells [10]. The onset of autoimmune diabetes is closely linked to the presence of specific autoantibodies, with anti-GAD65 being diagnostically the most common. Over 80% of individuals who develop T1D during childhood or adolescence test positive for this antibody. This antibody and similar antibodies are often present years before autoimmune diabetes becomes clinically apparent, suggesting a prolonged phase of autoimmune activity before diabetes actually develops [12]. There can be debate about the exact roles that GAD and anti-GAD65 play in the development of T1D. For example, T1D has been documented in patients with agammaglobulinemia, and anti-GAD65 antibodies can be found in the blood of infants born to anti-GAD65 positive mothers, including those who are diagnosed with T1D during pregnancy, even if the infants themselves do not develop diabetes [13].

A study comparing two health surveys around 11 years apart and selecting for individuals self-reporting as not having diabetes at that time or in the past in both surveys, which found around 4500 individuals, selected 76 people who tested positive for anti-GAD in the first survey. Around 54% of them became negative in the following survey [12]. However, there are not many cases in the literature about anti-GAD65 test results changing from positive to negative during a short time period, especially with T1D. There are several cases of T2D patients who show transient anti-GAD65 positivity following immunoglobulin administrations that later change to negative results [14-16]. This may result from different mechanisms, such as passively transferred antibodies, where the intravenous immunoglobulin made from pooled plasma passes autoantibodies from the donor. Another possibility is transiently triggered antibody production, where the immunoglobulin activates B cells, leading to an increase in plasmablasts and temporary antibody formation that causes a positive test result. These antibodies are likely non-harmful and typically decrease on their own within several weeks [14].

Another case reported temporary anti-GAD positivity in a patient with acute pancreatitis who also had a genetic haplotype associated with susceptibility to T1D. However, the patient's ability to produce insulin naturally was not impaired. The patient was anti-GAD negative a year prior, and levels of elastase-I were increased. Once the elastase-I levels and pancreatic swelling subsided, the anti-GAD levels returned to normal. This may have been triggered by the release of GAD antigen from damaged islet cells caused by pancreatitis, and the immunological response to it [13]. One case reported fulminant T1D with transient anti-GAD65 production. The patient presented with high blood glucose levels, ketonemia, and moderately increased HbA1c and glycoalbumin levels, among other abnormalities. He was initially treated with intravenous fluids and a continuous intravenous infusion of regular insulin, later changed to several insulin injections a day, with anti-GAD65 antibody measurements changing from 111 U/mL at the start, dropping to 22.8 U/mL after two weeks, and becoming negative after a year. The sudden and complete virally induced deterioration of beta cells, possibly causing the temporary rise in anti-GAD antibody levels, particularly in individuals with a genetically susceptible HLA class II haplotype like this patient [17].

Strict blood glucose control before and during pregnancy and careful adjustments to basal and bolus insulin doses help lower the risk of complications [1]. Though this maintenance and control of blood glucose in pregnant women with T1D leads to better health outcomes. However, striving for normal blood glucose levels can also pose risks, especially the increased likelihood of maternal hypoglycemia. Additionally, although achieving normal blood glucose levels is typically possible with treatment in cases of GDM and often in T2D, it is significantly more difficult in pregnant women with T1D and requires continuous management to avoid hypoglycemia [18]. A recent study showed that pregnant women with T1D had the most unstable glycemic profiles and a significantly more frequent hyper- and hypoglycemia records compared to those with T2D and GDM [19]. Females with pre-existing diabetes tend to experience more hyperglycemia complications during pregnancy than those with GDM, especially if high blood sugar isn’t properly managed. However, these risks can be reduced with pre-pregnancy counseling that focuses on keeping HbA1c levels close to normal, checking for existing complications, stopping harmful medications and habits, taking folic acid, and ensuring strict blood glucose control throughout pregnancy [19]. Pregnancies that could develop T1D should be identified and monitored for possible risks, as well as the sudden onset of diabetes after delivery. Those who test positive for anti-GAD should be seen as having a high risk of developing T1D and may be considered for potential immunomodulatory treatments in the future [10].

Conclusion

Blood glucose levels should be continuously monitored during pregnancy in anticipation of sudden changes. Autoantibodies like anti-GAD65 indicate the possibility of T1D, which can have adverse effects on both the mother and fetus, and should be considered and treated appropriately. 

Declarations

Conflicts of interest: The author(s) have no conflicts of interest to disclose.

Ethical approval: Not applicable.

Patient consent (participation and publication): Written informed consent was obtained from the patient for publication.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: SFA and RQS were significant contributors to the conception of the study and the literature search for related studies. TOS and SQO were involved in the literature review, study design, and manuscript writing.  HMM, NHAA, JMS, ANQ and KFH were involved in the literature review, the study's design, and the critical revision of the manuscript, and they participated in data collection. RQS and TOS confirm the authenticity of all the raw data. All authors approved the final version of the manuscript.

Use of AI: ChatGPT-3.5 was used to assist in language editing and improving the clarity of the manuscript. All content was reviewed and verified by the authors. Authors are fully responsible for the entire content of their manuscript.

Data availability statement: Not applicable.

Abstract

Introduction

Telemedicine is the remote delivery of healthcare services using information and communication technologies and has gained global recognition as a solution to address healthcare disparities. This study explores the perceptions of telemedicine and its potential to improve rural healthcare access in a developing country through the insights of undergraduate Medical Laboratory Science students.

Methods

A descriptive cross-sectional study was conducted among 42 fourth-year students of the Medical Laboratory Science program. Respondents completed a structured questionnaire that assessed their awareness, familiarity, perceived benefits and barriers to telemedicine, and their views on its applicability in rural Bayelsa.

Results

The findings indicated that while the majority of respondents (60.5%) were aware of telemedicine, their understanding of specific types, such as asynchronous and synchronous telehealth, was limited. The main perceived benefits were improved healthcare access (48.8%) and reduced costs (18.6%). Acceptance levels varied, with 47.6% endorsing telemedicine, while others remained uncertain or sceptical.

Conclusion

The study reveals enthusiasm and knowledge gaps among future healthcare professionals regarding telemedicine. It highlights the need for targeted education, digital literacy, and infrastructure investment to enable telemedicine in rural Nigerian communities.

Introduction

Telemedicine, the remote delivery of healthcare services using information and communication technologies (ICTs), has emerged as a transformative strategy for improving healthcare access, particularly in rural and underserved regions [1]. Overcoming geographical and logistical barriers enables timely consultations, diagnostics, and follow-up care without requiring long-distance travel.

In many developing countries, telemedicine has become an increasingly important solution for bridging healthcare gaps caused by workforce shortages, underdeveloped infrastructure, and rural-urban healthcare disparities. Low- and middle-income countries (LMICs) in Africa and Asia have seen gradual adoption of digital health technologies, including mobile health (mHealth) platforms and virtual consultations, especially during and after the COVID-19 pandemic [2]. While countries such as Rwanda, Ghana, and India have launched national digital health strategies, challenges like unreliable internet, funding limitations, and limited technical literacy continue to affect large-scale implementation [3]. Within this global context, Nigeria shares many of these challenges but also presents unique opportunities for leveraging telemedicine in improving rural healthcare access.

In Nigeria, where disparities in healthcare access are especially pronounced in rural areas, telemedicine holds considerable promise. Previous studies have demonstrated its benefits like reduced patient travel time and improved early diagnosis rates. Other studies found that telemedicine enhanced antenatal care coverage in rural communities in Enugu. These findings emphasise the potential of telemedicine in addressing healthcare disparities in diverse Nigerian settings [4,5].

However, the country's healthcare infrastructure and human resources remain critically inadequate, with a disproportionate concentration in urban areas [6]. Rural residents, who make up over 40% of the Nigerian population, face poor access to quality and affordable healthcare. Physical distance, limited transportation, and high travel costs often delay or prevent illness treatment, especially in geographically isolated areas [7]. These challenges have resulted in adverse health outcomes, including higher rates of infectious diseases and maternal and child mortality in rural communities. Telemedicine offers an opportunity to address these inequities by connecting healthcare providers with rural populations through virtual consultations and mobile health technologies [8]. Mobile platforms, in particular, facilitate affordable and convenient care delivery in settings lacking comprehensive health infrastructure.

While telemedicine has demonstrated significant potential in rural regions across Africa, successful implementation remains context-dependent, requiring adaptation to local infrastructure and socio-cultural realities [9]. Despite its benefits, the widespread adoption of telemedicine in Nigeria remains limited due to persistent challenges such as unreliable internet connectivity, the high cost of digital tools, and low levels of digital literacy among both healthcare workers and patients [10]. These challenges are even more pronounced in Bayelsa State, a region in Nigeria's Niger Delta known for its swampy terrain, scattered riverine communities, and poor road infrastructure [11,12]. Given these constraints, Bayelsa stands out as a strong candidate for targeted telemedicine interventions. However, there is a notable gap in data regarding local perceptions and readiness, particularly in these uniquely challenging settings.

In this context, telemedicine may enhance healthcare delivery by mitigating travel-related barriers through remote diagnostics, video consultations, and mobile health applications. However, developing effective implementation strategies requires an understanding of local awareness, perceptions, and barriers to the use of telemedicine.

In Nigeria, understanding local perceptions is critical to designing effective, context-specific telemedicine interventions. This study focuses on Bayelsa State, located in the country's Niger Delta region. It explores the perceived impact of telemedicine on healthcare access through the insights of 400-level Medical Laboratory Science students at Niger Delta University. These students represent a well-educated segment of the rural population, many of whom live in or maintain close ties with underserved communities. Their clinical training equips them with a foundational understanding of healthcare systems and digital innovations, such as telemedicine, allowing them to assess its applicability critically.

Furthermore, as future healthcare professionals, their perspectives offer valuable insight into both community needs and the likelihood of professional adoption of telemedicine. Their dual role as rural community members and emerging practitioners provides a unique vantage point for evaluating the feasibility, acceptance, and scalability of telemedicine. The findings aim to inform evidence-based policy and program strategies that could enhance healthcare access in geographically disadvantaged regions like Bayelsa State.

Methods

Study area

This study was conducted among 400-level students in the Department of Medical Laboratory Science at Niger Delta University, located in Bayelsa State, Nigeria. The university is situated in a region with significant rural and riverine communities, making it relevant for healthcare access and telemedicine research.

Study design

A descriptive cross-sectional study assessed perceptions of telemedicine and its potential impact on healthcare access in rural communities.

Population and sample size

The target population comprised all 400-level students enrolled in the Department of Medical Laboratory Science at Niger Delta University. Participants were selected based on their willingness and availability to respond to the questionnaire. This population was chosen because it represents a group of emerging healthcare professionals who are academically exposed to modern healthcare systems and likely to engage with digital health solutions in their future careers. As senior students in a clinical field, their perspectives offer valuable insights into the readiness and acceptance of telemedicine among the next generation of practitioners. Furthermore, their residence in Bayelsa State ensures contextual relevance, as they can relate professionally and personally to the healthcare access challenges faced in the region.

Data collection instruments

The primary instrument for data collection was a structured questionnaire developed using Google Forms. The questionnaire consisted of both closed-ended and open-ended questions designed to assess respondents' demographics, awareness of telemedicine, perceived benefits, challenges, and preferred access modes.

Data collection procedure

The Google Form link containing the questionnaire was distributed electronically via WhatsApp to prospective participants. Respondents accessed and completed the form using their electronic devices.

Statistical analysis

Descriptive statistics were used to summarise the data. The results are presented in tables and charts to illustrate key findings clearly.

Results

The majority of respondents were aged 21–25 years, indicating a predominance of young adults (Table 1). Most respondents were female (64.3%), while males comprised 35.7%.

The most frequently reported challenge to accessing healthcare was the high cost of healthcare services, cited by 50% of respondents. Other notable barriers included a shortage of medical personnel (21.4%) and long travel distances to healthcare facilities (14.3%). A smaller proportion of respondents either did not know where to access services (2.4%) or identified other issues, such as long wait times or inadequate infrastructure (11.9%) (Table 2). When asked what came to mind when thinking of telemedicine, 60.5% selected the combination of video calls, phone calls, and health applications. Smaller groups identified health apps alone (11.6%), phone calls (4.7%), or video calls (2.3%), while 20.9% indicated they were unfamiliar with the concept (Figure 1).

In terms of familiarity with specific types of telemedicine, 58.1% of respondents reported no awareness. Among the remaining respondents, 27.9% were familiar with mobile health (mHealth), 7% with remote monitoring, 4.7% with synchronous telehealth, and 2.3% with asynchronous telehealth (Figure 2).

Regarding the perceived benefits of telemedicine, 48.8% of respondents identified increased healthcare access as an important advantage. Other selected benefits included convenience (20.9%), reduced travel time and cost (18.6%), and improved health outcomes (9.3%). Only 2.4% selected "all the options" (Figure 3).

Discussion

Nigeria's healthcare system has consistently struggled to meet the demands of its rapidly growing population, which has surpassed 200 million [13,14].

Findings revealed that most respondents recognised telemedicine as involving video calls, phone calls, and health applications, indicating a broad level of general awareness. However, knowledge of specific categories such as asynchronous and synchronous telehealth was limited. This gap between general familiarity and specific understanding suggests the need for targeted education and capacity-building to support effective adoption of telemedicine services in rural communities.

The distribution of respondents across urban and rural backgrounds further underscored the relevance of telemedicine in both settings. However, its utility is particularly critical in rural areas where persistent barriers, such as travel distance, lack of transport, and shortage of healthcare professionals, continue to hinder timely access to care [15]. These issues are especially prevalent in geographically complex regions like Bayelsa State.

Healthcare-seeking behaviour among respondents also reflected patterns consistent with young adult populations, with many reporting infrequent visits to health facilities. This may be due to a combination of factors, including cost, convenience, and perceived need. Telemedicine presents an opportunity to address this behavioural trend by offering more accessible, flexible, and digitally enabled healthcare services suitable for this demographic.

Respondents identified high healthcare costs, shortage of medical personnel, and travel distance as the main barriers to accessing care. These findings align with previous research highlighting cost and provider shortages as critical obstacles to healthcare access in Nigeria [13-16]. In Bayelsa, the challenges are compounded by infrastructural limitations and rugged terrain. Telemedicine can mitigate these access issues by facilitating remote consultations, reducing the need for travel, and expanding the reach of healthcare professionals [17].

Although nearly half of the respondents expressed positive attitudes toward telemedicine, a significant portion remained either unsure or not in support. This suggests that awareness alone does not guarantee acceptance. Other factors, such as trust in virtual consultations, digital literacy levels, and user experience, may likely influence attitudes toward adoption. Similar findings in the literature indicate that successful implementation requires more than infrastructure; it must also involve building community trust and providing user-friendly, culturally appropriate solutions [18].

Supporting evidence confirms that a deeper understanding of telemedicine correlates with greater satisfaction and willingness to use digital health services [19]. The challenges reported in this study are consistent with known access barriers, reinforcing telemedicine's potential to address the structural limitations affecting rural healthcare delivery [16,20]. Prior studies have shown that telemedicine can reduce travel time, enable early diagnoses, and increase the efficiency of healthcare systems [15,19]. These benefits are particularly valuable in low-resource settings.

Interestingly, while much of the literature highlights internet connectivity and the cost of digital tools as primary barriers, respondents in this study placed more emphasis on the affordability and availability of healthcare services themselves [9]. This suggests that for students and communities in Bayelsa, immediate access to care is a more pressing concern than the infrastructure required to support digital health. In regions where core health services are still lacking, addressing foundational healthcare needs may take precedence over technological investments.
As with all self-reported data, there is a potential for response bias influenced by individual beliefs or differing levels of exposure to digital health tools.

Conclusion

The findings of this study broadly support existing literature affirming telemedicine's potential to improve healthcare access in Nigeria. The study underscores the need for context-specific, targeted strategies in implementing telemedicine, especially approaches that address affordability, community trust, and digital literacy. Future studies should examine broader stakeholder readiness, infrastructure challenges, and user training needs to guide effective policy and implementation.

Declarations

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

Ethical approval: This study was granted by the Research Ethics Committee of Niger Delta University.

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: None to be declared.

Authors' contributions: CFO conceptualised the idea and collected the data, while ELL wrote the manuscript and analysed the data. All authors read and approved the manuscript.

Use of AI: Grammarly was used to assist in language editing and improving clarity. All content was reviewed and verified by the authors.

Data availability statement: Not applicable.

Abstract

Introduction

There is a scarcity of reports on mixed lymphatic malformation. This case highlights a child with an extensive mixed lymphatic malformation, disfiguring multiple parts of the body.

Case presentation

A 3.5-year-old boy presented with multiple vesicular “frog-spawn” lesions that affected the right mid-axillary region, left axilla, and left upper back. The patient also had marked bilateral cervical swelling, extending laterally on both sides, with prominent bulges measuring approximately up to 10 cm that extended to involve the entire right upper limb dawn to the hand. Bilateral axillary swelling was observed. Additionally, swelling was evident in the entire middle and upper back, with a pronounced rounded bulge in the right upper back. Surgical intervention of the left axillary mass was performed, which was consistent with macrocystis lymphatic malformation on histopathology, but the condition recurred during follow-up.

Literature review

Few cases of microcystic lymphatic malformation with extensive deep lymphatic involvement have been reported in the literature. There was a female predilection with reported involvement of the forearm, thigh, vulva, axilla, jaw, and even the tongue. The patients' ages ranged from infancy to adulthood, with some patients complaining of skin lesions and recurrent cellulitis for years, sometimes leading to sepsis and death. There is variable outcome for surgical intervention in such cases.

Conclusion

Mixed lymphatic malformation can present extensively affecting several parts of the body causing significant disfigurement with possible recurrence after surgical intervention.

Introduction

The lymphatic system is essential for regulating plasma volume and preventing tissue pressure buildup, as it reabsorbs a significant portion of the fluid and proteins that leak out the blood vasculature. Additionally, it supports cell nutrition and aids the immune response by directing antigen-presenting cells to lymph nodes. In the skin, lymphatic vessels serve as a critical exit route for Langerhans cells [1]. Anomalies in the development of lymphatic channels can lead to various diseases, including lymphatic malformation which can be either localized or diffuse and may be either congenital or acquired [2]. Notably, lymphatic malformation shows no variation across racial groups, with up to 90% of cases diagnosed before the age of two [3].

The International Society for the Study of Vascular Anomalies (ISSVA) established a comprehensive classification system that categorizes vascular anomalies based on their clinical characteristics and whether they are accompanied by other symptoms, which includes cystic lymphatic malformation, Kaposiform lymphangiomatosis, Gorham–Stout disease, and Channel-type lymphangioma. The cystic type is further categorized into macrocystic lymphatic malformation (diameter greater than 1cm), microcystic lymphatic malformation (diameter less than 1cm), formerly called lymphangioma circumscriptum, and mixed cystic lymphatic malformation. Histologically, the lymphatic cysts may either appear empty or contain a protein-rich fluid abundant in lymphocytes and macrophages [3].

Cutaneous lymphatic malformation represents only 4% of all vascular tumors. Microcystic lymphatic malformation is an uncommon superficial variant that primarily affects the axilla, groin, thighs, and buttocks. The “frog-spawn” appearance is due to the distinguished formation of dispersed clusters of small, thin-walled, translucent vesicles on the skin. Additionally, microcystic lymphatic malformation may contain a prominent vascular or hemorrhagic component, causing the lesion's color to vary from pink to red to black, depending on the proportion of blood to lymph within the vesicles. The present report aims to describe a case of mixed lymphatic malformation with extensive involvement, disfiguring various parts of the body [4].

The current study was written in line with CaReL guidelines and the credibility of references has been verified using Kscien’s list [5,6].

Case Presentation

Patient information

A 3.5-year-old male presented with complaints of intermittent bleeding from skin lesions in the right axillary region. Additionally, the patient complained of extensive swelling in the neck, axilla, and upper back, and swelling of the right middle finger. There was no family history of similar skin lesions or swelling. The patient's past surgical history was notable for herniorrhaphy and axillary mass resection.

Physical examination

On physical examination, there were multiple skin-colored compressible masses on the neck, axillae, trunk, and upper limbs. On the axillae and upper back, there were multiple small groups of papulovesicular lesions with characteristic “frog-spawn” appearance with many bleeding points. The patient had marked bilateral cervical swelling, extending laterally on both sides of the neck, with prominent bulges measuring approximately up to 10 cm on each side, that extended to involve the entire right upper limb down to the hand. Bilateral axillary swelling was observed, accompanied by a scar in the left axilla, indicative of previous surgical intervention. Additionally, swelling was evident in the entire middle and upper back, with a pronounced rounded bulge in the right upper back. The swelling extended across the back, with slight marbling noted on the overlying skin. There was also swelling of the chest, most prominently around the sternum. In addition, there was swelling in the right middle finger (Figure 1).

Diagnostic approach

The skin lesions were diagnosed as microcystic lymphatic malformation (lymphangioma circumscriptum) based on their location, the characteristic appearance of the vesicular lesions, and the history of oozing blood. The involvement of deeper lymphatic system swelling further supported the diagnosis.

The laboratory blood investigations including complete blood count, thyroid stimulating hormone, C-reactive protein, and D-dimer were all within the reference range. Ultrasonography of the axilla and inguinal regions showed fairly symmetric, bilateral axillary soft tissue lesions with ill-defined, heterogeneous echogenicity, measuring approximately 8×4 cm. Small cystic areas were present within the lesions, with minimal internal vascularity but no evidence of phleboliths or prominent vessels. The sonographic features were non-specific, and potential differentials included hibernoma, lipoblastoma, and atypical hemangioma. A left axillary lymph node measuring 13×8 mm was noted; however, the bulk of the swelling was attributed to the soft tissue mass. No enlarged inguinal lymph nodes were observed, but a bilateral large inguinal hydrocele was present, along with bilateral undescended testes located in the inguinal regions. The other abdominal organs showed no abnormalities.

Contrast-enhanced computed tomography scan of the neck and upper chest showed normal lung parenchyma and a non-enhancing hypodense mass in the left axilla extending to the left supraclavicular region and a hypodense mass in the right side of the neck (Figure 2). The axillary magnetic resonance imaging (MRI) revealed bilateral symmetrical axillary masses, measuring 6×5×5 cm on the right and 6.5×5×4.5 cm on the left. These masses exhibited homogeneous high signal intensity on both T1 and T2-weighted images and were suppressed on fat-saturated sequences, with no enhancement post-contrast. The masses were associated with multiple enlarged axillary lymph nodes, the largest measuring 13×10 mm on the right and 13×9 mm on the left. Lipoblastoma was suggested as a differential, and biopsy was advised.

Biopsy of the axillary masses showed multiple fatty gray and tan pieces of tissue, the largest one measuring 85x80x40 mm. The microscopic sections showed multiple dilated cavernous and capillary size vascular spaces lined a by single layer of bland endothelium with flattened nuclei, surrounded by nodular aggregates of small mature lymphocytes and embedded in large lobules of mature adipose tissue, with areas that contain fetal-type skeletal muscle in process of maturation. There was no evidence of granulomata or invasive malignancy in the examined sections. Histopathology results were most consistent with macrocystic lymphatic malformation. A diagnosis of mixed lymphatic malformation was made.

Therapeutic intervention and follow-up

The patient previously underwent surgery to address the left axillary swelling; however, the lymphangioma recurred without significant improvement. Once-daily administration of sildenafil 10 mg and propranolol 10 mg yielded a good clinical response within the first three months, however on follow up there was an increase in the size of the mass. The frequency sildenafil dose was increased to 10 mg twice daily, and Pulsed Dye Laser (PDL) was applied for the microcystic lymphatic lesions for three sessions with no satisfactory response. At present, the patient is under observation with regular follow-up to monitor any potential complications or changes in the swellings that may require further intervention.

Discussion

The human skin comprises two distinct lymphatic plexuses. The superficial plexus, located near the subpapillary arterial network, consists of thin, non-valvular vessels extending into the dermal papillae. Lymph from this network drains into larger vessels situated in the lower dermis and the superficial subcutaneous tissue. The deep lymphatic plexus, positioned beneath the second arterial network, contains numerous valves and closely parallels the venous collecting system of the lower dermis [1].

The underlying pathophysiology of lymphatic malformation is characterized by fluid-filled muscular cisterns situated within the subcutaneous tissue, which establish a connection with the surface through dilated dermal lymphatic channels. Cutaneous involvement arises as a secondary consequence of the pressure exerted within the cisterns, driven by the pulsatile activity of their muscular walls. These cisterns do not communicate with the normal lymphatic system and lack any functional physiological purpose. The full extent of deep lymphangiomatosis cannot be accurately evaluated through physical examination alone, as the cisterns may extend significantly beyond the region occupied by the superficial vesicles [7]. For instance, a 13-year-old female reported by Palmer et al. complained of superficial lesions affecting the right inner thigh diagnosed as microcystic lymphangioma, but the right thigh had a 50cm thickness compared to the left side of 47.5cm. Further imaging revealed atypical expansion of the lymphatic channel stretching from the femoral region to the right para-aortic area [8]. Furthermore, a 15-year-old had more than 5 years of oozing from the microcystic lymphatic malformation affecting the left anteromedial inner thigh with deeper lymphatic involvement reaching the labia majora causing significant swelling and difficulty ambulating and disfigurement, during the literature review more cases have been identified with various parts of the body being affected (Table 1) [ 7-11].

The skin features of microcystic lymphangioma make its diagnosis straightforward but it can be misdiagnosed as other conditions, with a broad list of differential diagnoses including dermatitis herpetiformis, angiokeratoma circumscriptum, herpes simplex, herpes zoster, and hemangioma. In an interesting case by Juca et al, due to the verrucous appearance of the microcytic lymphangioma affecting a toe, leishmaniasis, skin tuberculosis, and warts were suspected first. However, histopathology was suggestive of microcystic lymphatic malformation showing convoluted ectatic lymph vessels in the papillary dermis [12]. Histopathology of the current patient revealed dilated vascular spaces lined by flat endothelium, surrounded by lymphoid aggregates, mature fat, and maturing fetal-type skeletal muscle.

Although lymphatic malformations are benign and typically a cosmetic concern, they can cause symptoms like burning, itching, and pain especially when complicated by infection, hemorrhage, or mechanical irritation. Leakage of blood-tinged, sometimes foul-smelling lymphatic fluid, either spontaneously or after minor trauma, can lead to discomfort and embarrassment. Open vesicles may also increase the risk of infection, leading to recurrent cellulitis and sometimes leading to sepsis and death. Due to cosmetic concerns, emotional distress, or frequent infections, patients often seek intervention [4,7]. Previously lymphangiogram was used to assess the extent of deeper lymphatic involvement as was the case by Palmer et al and Beard et al. Currently, computed tomography and magnetic resonance imaging are utilized more often [7-9]. For example, in the case report by Mordehai et al. computed tomography of a 1-month-old was shown to have a 3 cm cystic mass located in the anterior mediastinum, adjacent to the right side of the trachea and adherent to the superior vena cava. While on physical examination there was a group of vesicles on the right forearm with deeper cystic hygroma causing significant swelling of the right axilla. Interestingly, when wide excision of the axillary lymphangioma was carried out, the microcystic lymphatic malformation was then present at the site of the prior surgical site and suture lines with repeated episodes of cellulitis and lymphorrhea during the nine-year follow-up period [10]. Similarly, the current case had excision of the lymphangioma in the left axilla however, there was no recurrent cellulitis or vesicle formation at the scar site. The surgery was deemed ineffective as the deeper lymphatic involvement of the axilla recurred. Nonetheless, Surgical excision remains the primary treatment modality for the extensive/classical subtype, despite the potential for recurrence, as the surgical approach is predicated on the complete excision of all sequestrated lymphatic cisterns within the subcutaneous plane, as they are the principal etiological factor. The patient reported by Anees et al. resulted in good outcomes with no sign of recurrence 1.5 years after the operation of the medial left thigh. Other treatment modalities include intra-lesional sclerotherapy with doxycycline or Picibanil, as well as vaporization using carbon dioxide laser [9]. In a systematic review including 28 individuals with carbon dioxide laser ablation of microcystic lymphangioma, eight of them were disease-free and ten of them showed partial recurrence up to a three-year follow-up period, serving as an effective therapeutic option with a tolerable side-effect profile. Notably, it may also outperform surgical intervention for lesions with extensive surface area and deep involvement, though additional research is needed to confirm this advantage [4].

One limitation of our study is the absence of histopathological images, as only the histopathology reports were available. In addition, the relatively short follow-up period does not showcase the long-term physical and psychological outcomes of extensive mixed lymphatic malformation affecting several parts of the body​.

Conclusion

Mixed lymphatic malformation can present extensively affecting several parts of the body causing significant disfigurement with possible recurrence after surgical intervention.

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 the patient for publication.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: RSA and SOS were significant contributors to the conception of the study and the literature search for related studies. DH and JIH were involved in the literature review, study design, and manuscript writing.  LJM, OMH, SOA, DHBMS and FJS were involved in the literature review, the study's design, and the critical revision of the manuscript, and they participated in data collection. RSA and DH confirm the authenticity of all the raw data. All authors approved the final version of the manuscript.

Use of AI: ChatGPT-3.5 was used to assist in language editing and improving the clarity of the manuscript. All content was reviewed and verified by the authors. Authors are fully responsible for the entire content of their manuscript.

Data availability statement: Not applicable.

Abstract

Introduction

Alice in Wonderland Syndrome (AIWS) is an uncommon and frequently overlooked neuropsychiatric condition, marked by brief episodes of altered visual and somatosensory perception. This report presents a case of AIWS, highlighting the disorder's unusual nature.

Case presentation

A 21-year-old female sought evaluation due to episodic visual distortions and altered body perceptions lasting for six months, often accompanied by migraines. These episodes, including micropsia, macropsia, and derealization, typically occurred multiple times a week and lasted several minutes, with no clear triggers but worsening with stress or irregular sleep. She had a history of similar, less intense episodes in childhood. Neurological examination, MRI, EEG, and blood tests were all normal. She was diagnosed with AIWS related to her migraines and was prescribed propranolol, a stress management strategy, regular sleep, and cognitive behavioral therapy.

Literature review

Sixteen cases of AWIS were reviewed, of which only one had a family history of the condition. All of them experienced perceptual distortions, with macropsia and micropsia together appearing in eight cases, and hallucinations were present in four. Duration of symptoms ranged from one minute to one day. The triggering factors included Isolated cortical venous thrombosis and brucellosis. Treatments included lacosamide and paroxetine. Recurrence of symptoms was recorded in two patients.

Conclusion

Alice in Wonderland Syndrome is mostly a benign condition that can be resolved spontaneously or treated according to its associated cause; propranolol, improved sleep schedule, and cognitive behavioral therapy might yield good outcomes.

Introduction

Alice in Wonderland Syndrome (AIWS), first identified in 1955, is a rare perceptual disorder that causes significant distortions in how individuals perceive visual stimuli (metamorphopsias), their body image, and even the passage of time. Those affected may experience sensations such as seeing objects appear much larger or smaller than they are or feeling that their body is changing size [1]. The name of the syndrome is derived from Lewis Carroll's famous 19th-century novel Alice's Adventures in Wonderland, where the protagonist, Alice, experiences similar surreal phenomena, such as her body growing and shrinking, as well as other bizarre and disorienting occurrences. This condition is often described as a disruption in the brain's ability to process sensory input, leading to a distorted reality that can be confusing and disconcerting for the person experiencing it [2]. Although AIWS is rarely diagnosed, its actual prevalence may be underestimated, largely because clinicians often lack awareness of the condition, and patients, especially children, may struggle to describe their symptoms [3]. This condition is more commonly observed in younger individuals than in older adults [4]. After remaining relatively unnoticed for several decades, AIWS has recently started to gain scientific attention. This renewed focus is partly due to the advancement of functional imaging techniques, which now allow researchers to explore the brain's networks that mediate the disorder's symptoms [2,4]. Initially, AIWS was described in patients suffering from migraines and/or epilepsy and later found to be associated with temporoparietal lesions. It was also linked to psychiatric conditions such as depression and schizophrenia, as well as hypnagogic states and the use of various drugs, including hallucinogens and anticonvulsants [2]. Studies suggest that AIWS is usually a benign, self-limiting condition that resolves without the need for treatment [5].

This study aims to present a case of AIWS in a young adult with a history of migraines, emphasizing the outlandish and unusual nature of this disorder. The report was written following the CaReL guidelines, and only reliable, peer-reviewed sources were included while excluding any unreliable references or data [6,7].

Case presentation

Patient information

A 21-year-old female presented herself for evaluation at the suggestion of her family. She had experienced episodic visual distortions and disturbances in her perception of her body for six months. During these episodes, she said, her hands and feet appeared too large or too small, and the size and distance of everything around her seemed distorted. These episodes typically lasted several minutes and occurred multiple times a week, often coinciding with migraines. She was single and had sought help due to the frequency and disruption caused by these unusual perceptions.

The patient’s symptoms began approximately six months prior, without a clear trigger, involving visual distortions such as micropsia and macropsia, somesthetic distortions, and derealization. These episodes often coincided with migraines, characterized by unilateral headaches, photophobia, phonophobia, and nausea, resolving after several hours. The patient had no known triggers, though episodes were more frequent during stress or irregular sleep. Similar, less intense episodes occurred in childhood but were resolved by adolescence. The recent resurgence caused significant distress, prompting the patient to seek help.

The patient had no history of psychiatric illness, hospitalizations, or treatment, and had never used psychiatric medications. She was born at term with an unremarkable birth and past medical history, achieving all developmental milestones on time, with no early childhood illnesses or delays. She had a history of mild asthma treated with as-needed inhalers. There was no past head trauma, seizures, or infections, and the patient was healthy with no prior surgeries, and she also denied using alcohol, tobacco, or recreational drugs.

Mental state examination (MSE)

She was well-groomed and appropriately dressed. During the interview, she was cooperative and engaged, with no evidence of agitation or retardation. She was clear and coherent in her speech. With an anxious but congruent affect, she described feeling anxious due to the unpredictability of her symptoms. Her thought process was organized, goal-directed, and there was no evidence of thought disorder, delusions, or hallucinations. She described visual and somesthetic distortions consistent with Alice in Wonderland Syndrome, with no auditory hallucinations. Abounded with anxiety, but was eventually able to attend this socialization event. She exhibited good insight into her condition and preserved judgment.

Diagnostic investigation

The tests included MRI, EEG, and blood tests, all showing no abnormalities. Visual field testing was also normal, ruling out ocular causes for her symptoms. Given the normal test results, the diagnosis of AIWS was made based on the patient's reported symptoms and history of migraines.

Management

She was placed on prophylactic treatment with propranolol, a beta-blocker, to control her migraines. She was also advised to manage stress and maintain a consistent sleep schedule to reduce the likelihood of migraines. In addition, cognitive behavioral therapy was implemented to help combat the distress associated with her episodes.

Follow-up

After several months, both the frequency and intensity of her migraines diminished, and the severity of her AIWS episodes also lessened. Nonetheless, she continued to experience occasional perceptual distortions.

Discussion

In the existing literature, AIWS is typically described as a consequence of conditions like migraines, without leading to irreversible brain damage. However, infections have become the most commonly reported cause linked to AIWS cases, especially in children, surpassing migraines and epilepsy. Because of this, the exact nature of the lesions and the underlying pathology of AIWS remain difficult to identify and poorly understood [2,8].

AIWS symptoms have expanded to include 42 visual symptoms and 16 somesthetic and other nonvisual symptoms [1]. Individuals with AIWS experience changes in visual perception, such as micropsia (where objects appear smaller), macropsia (where objects appear larger), teleopsia (where objects seem farther away), and pelopsia (where objects seem closer). Similar to the reported case, all reviewed patients experienced perceptual distortions. Macropsia and micropsia occurred concurrently in nine cases, while hallucinations were reported in five. Incoherent speech, anxiety, and derealization were also noted as accompanying features of the visual distortions (Table 1) [3,4, 8-12].

Additionally, some patients with AIWS report abnormal changes in their perception of time, experiencing it as either speeding up or slowing down [2]. Distortions in the perception of time were present in the form of tachyopsia (environment moving or changing at an abnormally fast rate) in one of the reviewed cases [10]. Notably, a patient with AIWS is always aware that these distorted perceptions are not real, which distinguishes AIWS from conditions like psychosis, where the patient may perceive such distortions as part of their reality [2]. In AIWS, symptom duration is usually quite short, with each episode varying from less than 5 min to at most 30 min; however, 2 of the reviewed cases had episodes lasting up to 6 and 24 hours, adding another angle of uncertainty to this condition [8].

Kobayashi et al. reported 2 cases of AWIS, with lesions located in the right occipital lobe. To date, there have been about 10 cases of AWIS with bilateral or unilateral occipital lobe lesions [8]. While this finding suggests that occipital lesions may play a role in the development of AIWS, the majority of the cases do not involve brain damage. Similar to the reported case, 12 of the reviewed cases had no brain damage [3, 9-12]. Although several brain networks related to visual perception have been proposed as contributors to AIWS symptoms, imaging studies have not determined a clear cause, and some reports present conflicting results. However, the high number of reports linking migraine and epilepsy with AIWS suggests that an incomplete or widespread brain dysfunction may play a role in the development of the disorder [6].

Recent reports suggest that infectious diseases, particularly among children, are a leading cause of this Syndrome. These include Epstein-Barr virus, cytomegalovirus, Coxsackie virus B1, and varicella-zoster virus. The syndrome has also been linked to bacterial infections like Mycoplasma pneumoniae, Borrelia burgdorferi, and Streptococcus pyogenes, as well as protozoan and prion infections [2]. A case of AWIS associated with brucellosis was among the reviewed cases, adding to the increased infection-related cases [9].

Since 1955, fewer than 200 cases of AIWS have been recorded. However, the literature indicates that this may only represent a small fraction, as up to 30% of adolescents in the general population experience some of the individual symptoms of AIWS, albeit occasionally and briefly. [1]. Since it is not included in major classifications such as the ICD-10 or DSM-5, diagnosing AIWS depends on careful history-taking, a comprehensive physical examination (including neurologic and often otologic or ophthalmic assessments), and a good understanding of its diverse symptoms and possible causes. If a central origin is suspected, further tests like blood tests, EEG, and brain MRI are recommended, though the likelihood of identifying any observable lesions is generally considered low, as seen in the present case [1].

No specific treatment exists for AIWS; management generally focuses on addressing the underlying cause. Among the reviewed cases, interventions included beta-blockers, antipsychotics, antiepileptics, SSRIs, and supportive care, with symptoms resolving in 12 patients and recurrence noted in two [3,4,8-12]. Research indicates that antipsychotics are infrequently used in AIWS, and their effectiveness is generally considered limited. Moreover, when perceptual distortions occur alongside psychotic symptoms, it is important to note that antipsychotics, such as risperidone, may occasionally precipitate or exacerbate these distortions by lowering the threshold for epileptic activity [4]​.

Conclusion

AIWS is mostly a benign condition that can be resolved spontaneously or treated according to its associated cause; propranolol, improved sleep schedule, and cognitive behavioral therapy might yield good outcomes.

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 the patient for publication.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: YNA was a significant contributor to the conception of the study and the literature search for related studies. MMA was involved in the literature review, study design, and manuscript writing.  MQM, DAO, KAN, KKM, and SSA were involved in the literature review, the study's design, and the critical revision of the manuscript, and they participated in data collection. YNA and MMA confirm the authenticity of all the raw data. All authors approved the final version of the manuscript.

Use of AI: ChatGPT-3.5 was used to assist in language editing and improving the clarity of the manuscript. All content was reviewed and verified by the authors. Authors are fully responsible for the entire content of their manuscript.

Data availability statement: Not applicable.

Abstract

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a recently identified immune-mediated condition that is debilitating and often overlooked. While IgG4-RD has been reported in several organs, this study reviews cases where IgG4-RD caused pericarditis.

Methods

A systematic search was conducted from inception until March 1, 2025. All age groups and both sexes with confirmed pericarditis were included, along with the following inclusion criteria: 1) Patients with pericardial biopsy showing IgG4/IgG ratio of >40%. 2) Patients with pericardial biopsy revealing IgG4/HPF of >10. 3) Patients who had confirmed IgG4-RD from other organ biopsies through IgG4 staining, or diagnostic imaging suggestive of IgG4-RD, or pericardial biopsy with classic IgG4-RD histopathologic patterns, with elevated serum IgG4 levels, provided no other diagnosis was more likely.

Results

A total of 50 patients were included, with a mean age of 64.86±15.79 years. There were 36 (72%) males. The most common presenting symptom was dyspnea in 27 (54%) patients. Different pericardial involvements were reported, including pericardial thickening 37 (74%), constrictive pericarditis 28 (56%), pericardial effusion 23 (46%), pericardial calcification 6 (12%), and pericardial nodule 5 (10%). In 28 (56%) patients, only the pericardium was affected. In addition to the pericardium, eight (16%) patients had one other organ affected, and 11 (22%) patients had two additional organs affected. Two (4.5%) cases ended in demise.

Conclusion

Although rare, IgG4-RD can cause pericarditis, leading to pericardial thickening, effusion, constrictive pericarditis, or the formation of pericardial nodules. Treatment with corticosteroids or pericardiectomy has been associated with favorable outcomes.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory condition that affects multiple organs in the body. It is a slowly progressing and often debilitating disease, with the potential to be fatal in some cases [1]. The condition was first suspected in the pancreas where a subset of autoimmune pancreatitis was associated with elevated levels of serum IgG4, now termed autoimmune pancreatitis type I [2]. The discovery that individuals with autoimmune pancreatitis also develop extra-pancreatic fibroinflammatory lesions containing abundant IgG4-bearing cells, in addition to histopathological features consistent with that in the pancreas, which include; dense lymphoplasmacytic infiltration, storiform fibrosis, and either obliterative or non-obliterative phlebitis, contributed to the establishment of the concept of IgG4-RD as a unique clinical entity in 2003 [1-3]. For decades, conditions such as Riedel thyroiditis, sclerosing cholangitis, Mikulicz’s syndrome, hypertrophic pachymeningitis, and retroperitoneal fibrosis were considered distinct entities. However, they are now classified within the spectrum of IgG4-RD, as they have been found to share similar histologic features and present concurrently in some patients [4].

The worldwide prevalence and incidence of IgG4-RD are mostly underreported. Still, studies from Japan have revealed that the incidence of autoimmune pancreatitis increased from 0.8 to 3.1 cases per 100,000 people between 2007 and 2016, suggesting a swift rise in recognition of IgG4-RD within just a decade [4]. There is a higher prevalence among males, with the average age at diagnosis typically ranging from the fifth to sixth decade of life. However, classic presentations have also been documented in pediatric patients [1]. Cigarette smoking is the only well-documented modifiable risk factor associated with the development of IgG4-RD [5]. A genome-wide association study revealed that the FC-γ receptor IIb and HLA-DRB1 regions were associated with an increased susceptibility to IgG4-RD, indicating a potential genetic predisposition to its pathogenesis [6].

The pathophysiology of IgG4-RD remains incompletely understood. However, several critical components have been identified, including the migration of activated B cells to the site of inflammation, where they facilitate the expansion and differentiation of T cells into CD4+ cytotoxic T lymphocytes (CTLs). These CD4+ CTLs subsequently induce apoptosis by releasing perforins and granzymes. In response, activated M2 macrophages clear the apoptotic cells while also contributing to the activation of fibroblasts. This activation is promoted through several mediators, including IFN-γ (interferon-gamma), TGF-β (transforming growth factor-beta), and IL-1 (interleukin-1) from CD4+ CTLs, along with PDGF (platelet-derived growth factor) from activated B cells, and various factors from macrophages. As fibroblasts become activated, they secrete extracellular matrix proteins, leading to tissue remodeling and fibrosis. Over time, the progressive expansion of the extracellular matrix and increased cell proliferation contribute to the development of tumor-like masses and the subsequent enlargement of affected organs, as observed in clinical settings [7].

While IgG4-RD has been reported in multiple organs, this study is the first to comprehensively review cases where it affects the pericardium, leading to pericarditis.

Methods

Study design

The present systematic review was conducted per the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Literature search

A thorough systematic search was conducted across Scopus, PubMed, Web of Science, and Google Scholar databases to retrieve studies published from inception until March 1, 2025. The search employed the following keywords: “IgG4 OR IgG4RD OR immunoglobulin AND pericarditis OR tamponade OR pericardial OR pericardium OR serositis OR serosal”

Eligibility criteria

The inclusion criteria were restricted to English-language publications involving only human subjects, specifically case-control studies, cohort studies, cross-sectional studies, or case reports. Additionally, due to the limited number of studies on this topic, conference papers containing adequate information were also included.

All age groups, both sexes, with confirmed pericarditis through a combination of clinical examination, ECG (electrocardiography), diagnostic imaging (including echocardiography, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET)), laboratory investigations, or histopathological examination of the pericardial tissue or fluid were included.  Given the limited number of reports on this entity and a lack of standardized diagnostic criteria for IgG4-RD pericarditis, such as an established IgG4/IgG ratio or IgG4/high power field (HPF) in pericardial specimens or its necessity in the first place when other clues are suggestive of this disease, this review adopted an inclusive approach. With patients of either of the following criteria being included: 1) Patients with pericardial biopsy showing an IgG4/IgG ratio of >40% or reported as “increased”. 2) Patients with pericardial biopsy revealing IgG4/HPF of >10 or reported as “increased”. 3) Patients who had confirmed IgG4-RD from other organ biopsies through IgG4 staining, or diagnostic imaging suggestive of IgG4-RD, or pericardial biopsy with classic IgG4-RD histopathologic patterns, with elevated serum IgG4 levels, provided no other diagnosis was more likely.

The exclusion criteria included studies with incomplete information about the patients or the method of diagnosis. Patients who were more likely to have pericarditis due to causes other than IgG4-RD. Studies from journals with inadequate peer review and questionable reliability were excluded [8].

Study selection

The screening process commenced with two independent researchers who systematically reviewed the titles and abstracts of all identified studies. Following this initial assessment, a comprehensive full-text evaluation was conducted based on predefined inclusion and exclusion criteria. Studies that satisfied these eligibility criteria were subsequently selected for inclusion. In instances where disagreements emerged between the two researchers, a third author was consulted to mediate and resolve conflicts through discussion and consensus.

Data items

Data extraction was conducted using Microsoft Office Excel 2016. The following variables were collected for each study: first author’s name, year of publication, study design, country of origin, sample size, patient sex, age, past medical and surgical history, family history, presenting complaint, and duration of symptoms. Additionally, data regarding pericardial involvement were extracted, including the presence of pericardial thickening, constrictive physiology, pericardial calcification, and pericardial nodules. The presence or absence of pleural disease was also recorded.

If available, findings from diagnostic imaging modalities such as chest radiography, echocardiography, CT, MRI, PET, and right heart catheterization were documented. Laboratory results, when reported, were extracted for C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR), N-terminal pro-brain natriuretic peptide (NT-proBNP), serum IgG4 levels, serum IgG4/IgG ratio, and any other notable laboratory parameters.

Furthermore, the number of organs affected by IgG4-RD, and the histopathological findings were collected. Treatment modalities, including both successful and unsuccessful interventions, were documented, along with follow-up duration and clinical outcomes.

Data analysis

The data were analyzed using the Statistical Package for Social Sciences (SPSS) version 26.0, which facilitated the quantitative synthesis of the information. Relevant variables were displayed in summary tables, with categorical data represented by frequency and percentage, and quantitative data summarized using the mean and standard deviation.

Results

Study selection

The literature search yielded 87 studies from the databases. During the initial screening, one study was removed due to duplication, four for being in a non-English language, and four were closed access/unretrievable. The 78 studies remained for screening through titles and abstracts. Of these, eleven were excluded from the title and three from the abstract due to irrelevancy.

During the full-text screening, two retrospective cohort studies were excluded even though they included patients with IgG4-RD causing pericarditis. As those studies also included patients with IgG4-RD affecting other organs without pericardial involvement. However, they did not provide specific details on the characteristics, diagnostic workup, or histopathological findings of IgG4-RD in the subset of patients with pericarditis. As a result, they did not meet the inclusion criteria for this systematic review. One study was excluded as there was insufficient information to diagnose IgG4-RD. Additionally, two other studies were excluded after the full-text screening because they did not report IgG4-RD as a cause of pericarditis. Letters to the editor and preprints were excluded, with six and one paper removed respectively. Two studies were excluded from journals with inadequate peer review. Ultimately a total of 50 studies were included in the current systematic review for analysis (Figure 1).

Characteristics of the studies

Of the included studies, 40 (80%) were case reports, and ten (20%) were conference abstracts. Japan 22 (44%) and the United States of America 17 (34%) had the most publications, followed by Korea 3 (6%), the other studies were all from different countries (Table 1, Table 2, Table 3) [9-58].