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An important condition in gynecology and endocrinology is primary amenorrhea which has many complicated causes. This research captures most of the causes in females presenting to a tertiary care center as Müllerian agenesis, gonadal dysgenesis, hypogonadotropic hypogonadism and Turner syndrome. This study highlights the value of thorough clinical assessment as well as the need for supportive hormonal, radiological, and genetic analyses. Insight into the various causes aids in the improvement of management and reproductive health and helps lessen the psychosocial burden. It is imperative that more studies of this kind be conducted so that local data may provide a basis for diagnostic and management protocols.

This study analyzed causes and occurrence of primary amenorrhea in females who visited a tertiary health care center in Karachi. Müllerian agenesis was the most prevalent cause. This was followed by gonadal dysgenesis, hypogonadotropic hypogonadism and Turner’s syndrome. This study’s findings concord with the international literature which demonstrates that congenital anomalies of the reproductive tract and gonadal disorders are the major causes of primary amenorrhea. {6,7}

This study also found that the majority of females with primary amenorrhea had Müllerian agenesis. Peeyananjarassri et al. also found that the majority of females with primary amenorrhea had Müllerian agenesis when they studied females who presented to a tertiary health care facility.{5} Similarly, in a multicenter study, Kim et al. found that approximately 25% of the patients had Müllerian agenesis and classified this as the leading diagnosis of the national cohort.{4} Müllerian agenesis is most likely the leading congenital cause of primary amenorrhea due to the fact that affected females with primary amenorrhea may develop secondary sexual characteristics, and due to the presence of normal ovaries, may have normal pubertal development. This may also lead to a delay in diagnosis until the female is in her teens.{7}

In this study, gonadal dysgenesis was the second leading cause of primary amenorrhea. Similar to Europe and Asian studies, the majority of primary amenorrhea cases studied also had Turner’s syndrome.{4,8} Turner’s syndrome is one of the most frequently diagnosed gonadal disorders and is also associated with primary amenorrhea.{9} Numerous studies have also demonstrated that hypogonadotropic hypogonadism is also a frequent diagnosis.{9}

Hypothalamic dysfunction may be due to various congenital causes, chronic diseases, nutritional deficiencies, excessive exercise, or psychosocial stressors. {10} Disruption of gonadotropin-releasing hormone causes lack of stimulation of the pituitary-gonadal axis, resulting in lack of pubertal development and menstruation. Due to changes in lifestyle and diet, functional hypothalamic amenorrhea is more widely recognized in adolescents. {11}

Etiological factors provide evidence for the need to include clinical evaluation, laboratory hormonal tests, imaging, and genetic analysis in a comprehensive diagnostic evaluation. The potential consequences of a delayed diagnosis on reproductive health, bone health, psychosocial health, and the potential of future fertility should be considered when determining the priority for an in-depth evaluation of the diagnosis. {12, 13 }

This study was based at the Jinnah Postgraduate Medical Centre (JPMC) in Karachi, Pakistan. The study subjects were female patients with primary amenorrhea. This study focused on patients in the outpatient and inpatient departments of the JPMC.

The study used the WHO sample size estimation formula with an expected prevalence of 26.2% reported by Kim et al. in a multicenter study of 856 patients. The sample size was calculated with a 95% confidence interval and a 5% margin of error. Based on this formula, the sample size was 297 patients.

Data collection was based on a non-probability consecutive sampling method. This study included participants who met the study criteria.

In this study, female patients 13-25 years of age with primary amenorrhea were included, which is defined as the absence of the first menstruation (menarche) by the age of 15 if there are normal secondary sexual characteristics, or by the age of 13 if there are no secondary sexual characteristics. Patients with secondary amenorrhea, previously diagnosed and treated causes of amenorrhea, severe and chronic illness that interfered with a full and thorough evaluation, incomplete diagnostic evaluation, and those who refused to participate in the study were also excluded.

Following acquisition of written informed consent, demographic and clinical data were collected as per a predesigned data collection tool. A detailed clinical history was taken to include the age of presentation, family history, development history, and other associated symptoms. A complete clinical examination was performed focusing on the secondary sexual characteristics. Relevant laboratory tests were reviewed. Pelvic ultrasound was performed on all patients. MRI and karyotyping were performed as per requirement. The consultant gynecologist provided the definitive diagnosis of the clinical findings and the required investigations.

The variables for this study were the age, body mass index, secondary sexual characteristics, hormonal levels, imaging findings, karyotype, and the cause of primary amenorrhea. The causes were classified as Müllerian anomalies, gonadal dysgenesis, hypothalamic-pituitary disorders, estrogen-related disorders, missed puberty, disorders of sex differentiation, and other causes.

Data was analyzed using the Statistical Package for the Social Sciences (SPSS) version 26. Quantitative data was age and body mass index and was expressed as mean and standard deviation. Qualitative data was the cause of primary amenorrhea and was expressed as frequency and percentages. Effect modifiers were stratified where applicable. A p value of less than 0.05 was significant.

Prior to the study, ethical approval was acquired from the Institutional Review Board/Ethical Review Committee of Jinnah Postgraduate Medical Centre, Karachi. Informed consent was gained from all participants and/or their legal guardians. Participant’s information remained confidential and anonymous throughout the course of the study. All procedures were in agreement with the ethical principles of the Declaration of Helsinki.

The sample for this cross-sectional study was drawn from the Outpatient and Inpatient Departments of the Obstetrics and Gynecology Division at the Jinnah Postgraduate Medical Center in Karachi, Pakistan, and included female patients with primary amenorrhea.

The sample size was determined using the WHO sample size estimation formula. A 95% confidence level, 5% margin of error, and the prevalence of Müllerian agenesis at 26.2% among primary amenorrhea patients in the study by Kim et al. (who analyzed 856 patients in 8 different centers) was used. Based on this information, the sample size was calculated to be 297 patients.

The study used a non-probability consecutive sampling design to recruit participants that met the inclusion criteria.

The study included female patients aged 13-25 years that met the primary amenorrhea definition of the absence of menarche (15 years) with normal secondary sexual characteristics, or the absence of secondary sexual characteristics with amenorrhea by 13 years. The study excluded patients with secondary amenorrhea, amenorrhea of previously diagnosed and treated causes, patients with serious or chronic illness that prevented a complete assessment of the patient, or participants that refused to give consent.

Demographic and clinical details were documented on a custom data collection tool, after documented informed consent, and a thorough history was recorded, including age of presentation, family and developmental histories as well as any accompanying symptoms. A thorough physical exam was performed, with special consideration to the presence of secondary sexual characteristics and a genital exam, when appropriate. Pertinent lab tests, including serum follicle stimulating hormone, luteinizing hormone, estradiol, and prolactin, as well as thyroid stimulating hormone and other hormonal assays, were evaluated. All patients had pelvic ultrasounds, and when indicated, magnetic resonance imaging and karyotyping were performed. The consultant gynecologist formulated the final clinical diagnosis after thorough clinical and diagnostic assessment.

Study variables included age, body mass index, presence of secondary sexual characteristics, hormonal profiles, imaging results, karyotyping results, and the definitive diagnosis of primary amenorrhea. The etiological classification included Müllerian agenesis, gonadal dysgenesis, hypothalamic-pituitary amenorrhea, endocrine causes, constitutional delay of growth and development, a disorder of sex development, and other causes.

Data was analyzed using Statistical Package for Social Sciences (SPSS) version 26. Means and standard deviations were reported for age and body mass index. Frequencies and percentages were reported for qualitative variables, and etiological groups were classified. Effect modifiers were stratified. A p-value of less than 0.05 was statistically significant.

Prior to starting the study, ethical approval was granted by the Institutional Review Board/Ethical Review Committee of Jinnah Postgraduate Medical Centre, Karachi. Informed written consent was obtained from all participants and/or their legal guardians. participant data was kept confidential and anonymous. All procedures complied with the ethical principles of the Declaration of Helsinki.

Primary amenorrhea is the absence of menstruation by the age of 15 for girls with fully formed secondary sexual characteristics or by the age of 13 for girls with no signs of puberty. It is clinically highly significant because it is indicative of underlying disorders associated with reproductive organs, the endocrine system, genetics, or anatomy. All of these conditions require urgent assessment because of the negative reproductive and psychosocial effects they may have. Even though it is rare, primary amenorrhea is a major global reproductive health challenge. It is estimated to affect 0.1% of the adolescent female population, but there is a lot of variability in prevalence depending on the population and local health system.{2}

Causes of primary amenorrhea can be aplastic or hypoplastic conditions affecting any level of the HPO axis, gonadal disorders, congenital reproductive tract malformations, or disorders of sex development. Recent studies found that the major global causes of primary amenorrhea are Müllerian agenesis, gonadal dysgenesis, Turner syndrome, and hypogonadotropic hypogonadism with a constitutional delay of puberty.{3,4} In a large multicenter study of 856 primary amenorrhea cases, Müllerian agenesis was the most common cause in 26.2% of cases, and gonadal dysgenesis was the cause in 22.4% of cases, showing the prevalence of congenital and chromosomal abnormalities in these women.{4} In recent studies, Turner syndrome and Müllerian agenesis were the most common causes of primary amenorrhea.{5,6}

The primary amenorrhea causes reflect the local conditions most influenced by the local genetics, environment, social conditions, and health care. For this reason, local data on the epidemiology of primary amenorrhea and its causes are needed to guide the development of the best diagnostic methods and treatment for the patients.{4,5}

Nonetheless, research on the frequency and underlying causes of primary amenorrhea in Pakistani females at tertiary care hospitals is highly scarce.

For this reason, this study was conducted at the Jinnah Postgraduate Medical Centre (JPMC), Karachi, to assess the frequency and causes of primary amenorrhea among females presenting to JPMC.

This study aims to provide local evidence in order to enhance the clinical management of the patients and help in the early diagnosis and workup of the patients.

Asherman's syndrome is the most extreme form of uterine scarring, presenting with varying degrees of primary infertility. In the most classic sense, patients present with the triad of symptoms of amenorrhea, cramping, dysmenorrhea, and infertility. Menorrhagia can occur in the presence of a hematometra and is commonly seen with recruited endometrial tissue in the presence of Asherman's syndrome. Acute onset of abdominal pain can occur when a trapped endometrial tissue becomes infected or ruptures an associated hematometra. The patency and the dimension of the uterine cavity determine the infertility seen with the syndrome.

The most prevalent type of Asherman's syndrome is the intrauterine adhesion of type 1 that is diagnosed because of the aforementioned complaints. The presence of severe forms of type 2 Asherman's syndrome is rare. There are different classifications of Asherman's syndrome but the most accepted is the American Fertility Society that identifies three major types: class I (mild) in which there are single endometrial tissue adhesions that do not obstruct the uterine cavity, class II (moderate) where uterine cavity obstruction is present, and class III (severe) where complete obstruction occurs.

About 10% of patients with Asherman's syndrome can become pregnant spontaneously, and those that do report infertility will eventually achieve a pregnancy. Many patients report symptoms of amenorrhea and infertility, but as with other patients with hypomenorrhea, postpartum or post surgical amenorrhea can become a symptom and should be evaluated.

There are few studies that discuss the prevalence and causes of primary amenorrhea in females attending tertiary care facilities in Pakistan.

For this reason, we analyzed the frequency and causes of primary amenorrhea in females presenting to Jinnah Postgraduate Medical Center in Karachi, Pakistan. We anticipate that our findings will help clinicians develop and execute more timely and appropriate diagnostic and therapeutic strategies.

Intensive care unit (ICU) admission due to obstetric complications continues to present a major concern regarding severe maternal morbidity. The need for ICU care at the postpartum period was mainly due to postpartum hemorrhage and/or the hypertensive disorders of pregnancy. Fortunately, most patients benefited from the therapeutic effects of specialized critical care management. The survival of a larger number of mothers at the end of the multidisciplinary approach is a reflection of the improved management of high-risk pregnancies and the shift of care to a higher level. Formation of the emergency obstetric care pathways and strengthening of the current antenatal care may further reduce the burden of severe maternal complications. The need for larger, multicenter investigations is highly warranted in order to develop evidence-based maternal healthcare policies.

This study examined the incidence and risk factors associated with severe pregnancy complications that result in an obstetric patient being admitted to an intensive care unit (ICU) and the resultant survival outcomes. The findings indicated that the majority of obstetric patients who were admitted to the ICU, but later discharged, were admitted for postpartum hemorrhage and pregnancy induced hypertension disorders. These findings correlate with the existing literature that demonstrates that obstetric hemorrhage and pregnancy induced hypertension disorders are the leading causes of severe maternal morbidity in the world that requires critical care {7,8}.

From the findings of this study, postpartum hemorrhage was the leading cause for ICU admission. Similar findings have been documented in other studies conducted in low and middle income countries (LMICs) where there are obstacles in the referral system, emergency obstetric care, and Blood Transfusion services {9,10}. Severe maternal hemorrhage can cause hypovolemic shock and disseminated intravascular coagulopathy (DIC) that cascade into multiple organ failure making Maternal Intensive Care (MIC) a necessity {11}. The importance of early detection is underscored in order to decrease maternal morbidity and mortality.

Another leading cause for ICU admission was noted to be pregnancy induced hypertension disorders (PIH), preeclampsia and eclampsia. These findings are consistent with the global reports and the documented severe maternal critical disease caused by severe hypertension {12,13}. The leading pathophysiological mechanisms of this disorder are systemic inflammation and placental vascular dysregulation that becomes a critical care disorder due to dual organ system failure and edema {13}.

The study recorded overall survival rates that were favorable and comparable to those recorded in studies undertaken in tertiary care centers where multidisciplinary obstetric critical care has been established {14}. There are several reasons survival rates may have improved, and include maternal multi-disciplinary team members’ increased collaboration, maternal care advancements, and the obstetric teams’ willingness to be proactive {15}. Recent studies have shown that maternal early warning systems have more likely than not assisted in the rapid recognition of the deterioration of an expectant mother’s health status and resulted in improved maternal health care outcomes {16}.

The study recognized that the presence of antenatal care lessened the development of complications in pregnant women. It is especially true of women who received inadequate antenatal care. Regular antenatal care is more likely than not to lead to timely detection of elevated blood pressure, severe anemia, and other health conditions, which if left untreated, would progress to become life-threatening {17}. It is likely that improvement of maternal health care services would lessen the need for obstetric ICU Services.

There are several recognized strengths to the study. The study successfully described critical care of obstetric patients in a tertiary care setting and included survival outcome assessments as well {17}. The study also included major maternal multi-disciplinary team care foci and included an evaluation of each described support.

There are some limitations that need to be discussed in the context of these findings. Since only one tertiary care center was used, these findings may not be applicable to other health care systems. The small sample size may contribute to the inability to detect more infrequent risk factors that may lead to adverse outcomes. Additionally, the extraction of clinical data from medical records was done retrospectively and may have been impacted by incomplete documentation and information bias.

The findings of this study are important. The early detection of women who are at risk of developing severe obstetric complications, as well as the strengthening of antenatal care, and the improvement of obstetric referral systems and multidisciplinary critical care can all contribute to a decrease in maternal morbidity and mortality. Further, larger, multi-center studies are needed to evaluate the impact of maternal obstetric complications on the admission to the ICU and the long-term outcomes of these women.

This study aimed to describe the characteristics of obstetric patients admitted to the Intensive Care Unit (ICU) of the Department of Obstetrics and Gynaecology at the Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan. JPMC is a tertiary care hospital. The study was conducted over a period of six months with the permission of the College of Physicians and Surgeons Pakistan (CPSP) and the Institutional Ethical Review Committee.

The patients selected for the study were those admitted to the Obstetrics and Gynaecology ICU due to complications of pregnancy during the antenatal, intrapartum, or postpartum periods (within 42 days of delivery). The sample size was determined to be 47 using the WHO sample size estimation formula for a proportion, with a 12% proportion of ICU admissions, a confidence interval of 95% (Z = 1.96), and an 8% margin of error, as stated in the parent study. Non-probability consecutive sampling was done, and all patients who met the eligibility criteria and were admitted to the ICU during the study period were enrolled, until the sample size of 47 was met.

Women between 18 to 45 years of age and admitted to the ICU due to obstetric complications were included in the study. Patients who were admitted and/or remained in the ICU for non-obstetric reasons, such as trauma or poisoning, and patients whose medical records were not complete were excluded from the study.

A structured proforma designed for this study was used to collect data retrospectively from patients’ medical records. An array of data was captured that included demographic details and information related to the obstetric history, antenatal care status, reasons for ICU admission, types of obstetric complications, treatments in ICU, length of stay in ICU, and patient outcomes. Postpartum hemorrhage, hypertensive complications of pregnancy (preeclampsia and eclampsia), pregnancy related sepsis and cardiac complications were the major obstetric complications documented. The primary outcome of the study was the survival status upon discharge from the ICU, which was classified as survived (discharged alive) or not.

The independent variables included age, parity, antenatal care status, type of obstetric complication, method of delivery, length of stay in the ICU and the therapeutic interventions received. The dependent variables were obstetric complication related ICU admission and the outcome of the ICU stay.

Data were analyzed using the 25th version of the Statistical Package for the Social Sciences (SPSS). Standard descriptive statistics were performed for each study variable. Categorical data were summarized using frequency and percentage distribution while continuous data were summarized using mean and standard deviation. The Chi-square test was used to determine the associations between risk factors and survival outcomes. Relating to survival outcomes, factors were assessed for statistically significant association using logistic regression analysis. A p-value of less than 0.05 was accepted as significant.

The study was granted ethical approval by the Jinnah Postgraduate Medical Centre and CPSP Institutional Committees. Data anonymity was utilized to ensure patient confidentiality. Collected data and records were only accessible to the research team. No direct patient interaction or intervention took place, and all procedures were in alignment with the Declaration of Helsinki ethical principles.

Patients with obstetric complications requiring Intensive Care Unit (ICU) admission represent a small, but extremely vulnerable, group of patients with severe maternal morbidity and an elevated risk of maternal mortality. Significant improvements in obstetric and critical care subspecialties have reduced some of the severe life-threatening maternal complications, yet there are important and significant contributions to global maternal morbidity from severe life-threatening complications of pregnancy, childbirth, and the postpartum period. Admission to an ICU is a well-established, objective marker of severe maternal morbidity and indicates the burden of critical maternal illness on the healthcare system {1}.

A recent systematic review and meta-analysis of more than 41 million deliveries estimated an overall ICU admission rate of 1.6% for pregnant and postpartum women, with significant differences between high-income (0.4%) and low- and middle-income countries (2.8%) {2}. These differences are due to differences in the stages of care within the healthcare system and in the availability of and access to specialized care. The most common reasons for ICU admission are hypertensive disorders of pregnancy, obstetric hemorrhage, sepsis, and cardiovascular disorders {3, 4}. The most common reason for ICU admission in a study of critically ill obstetric patients in multiple centers was postpartum hemorrhage and hypertensive disorders, demonstrating the high burden of these disorders in maternal morbidity {5}. It is also important to note that maternal mortality among obstetric ICU admissions in sub-Saharan Africa was estimated to be 30.7%, demonstrating the high burden of maternal morbidity in resource-limited countries {6}.

To enhance the quality of maternal health services, it is important to explore the factors contributing to the admission of mothers to intensive care units (ICUs) as well as the factors related to their survival post-admission. A number of studies have shown that obstructed referrals, poor prenatal care, aggravated hemorrhage, and sepsis with multiple organ failure have negative end results in critically ill obstetric patients {4,6}. However, there is a scarcity of literature from Pakistan concerning the situation and outcome of obstetric patients admitted to ICUs of tertiary care hospitals.

Patients needing obstetric care during their ICU stay form a small but at-risk population representing patients with severe maternal morbidity with a high risk of mortality. While maternal care has improved in both obstetric and critical care settings, complications that are life-threatening during the ante-, intra-, and post-natal periods continue to be a major concern to maternal morbidity globally. Admission to the ICU has become an accepted objective indicator of severe maternal morbidity and comprises the burden of critical obstetric care on the health system.

A systematic review and meta-analysis of 41 million obstetric admissions reported that on average 1.6% of pregnant and postpartum women were admitted to the ICU, with large disparities based on the income of the countries where 0.4% of ICU admissions were from high-income countries compared to 2.8% from low and middle-income countries. The disparities are most likely due to differences in the availability and accessibility of specialized obstetric care. The main indications for ICUs for obstetric care globally remain care for hypertensive disorders, obstetric hemorrhage, infection, and care for the cardiovascular system. ICUs for critical care for obstetrics in multi-centered studies pointed to postpartum hemorrhage and hypertensive disorders as the main contributors to maternal morbidity. A recent maternal ICU admission study from Africa showed a pooled maternal mortality of 30.7% thus exhibiting the burden of critical care for obstetrics in low resource settings.

An understanding of the determinants of ICU admittance, along with survivor outcomes, is critical to enhancing the system of maternal healthcare. Previous literature has shown that, among critically ill obstetric patients, adverse outcomes have been associated with late referrals, poor antenatal care, severe obstetric hemorrhage, sepsis and multiple organ failure {4,6}. However, with the exception of some studies, there is a scarcity of literature from Pakistan, especially with regard to the incidence, risk factors and survivor outcomes of obstetric ICU admissions in tertiary care hospitals.

Discussion:

Chronic Superior vena cava (SVC) syndrome is a well-known and established condition caused by cardiac implantable electronic devices (CIEDs) but is certainly a rare condition. It primarily has been seen in patients with multiple transvenous leads and repeat device surgeries. Venous stenosis is present in many patients with a pacemaker. It is most often asymptomatic, but if patients develop symptomatic SVC syndrome, it most often occurs years after lead placement. It is hypothesized that transvenous CIED leads injury the endothelium and along with inflammation and fibrosis cause chronic stenosis of the vein.

This case illustrates a unique scenario in that the diagnosis evolved from what was believed to be acute SVC thrombosis to chronic lead associated SVC stenosis, and possibly, superimposed thrombosis. The first cross-sectional venous imaging demonstrated venous thrombosis, thus venous therapy was initiated. However, the development of symptoms, as well as the findings of venous surgery/intervention, suggested a chronic process. In some of the earlier studies, the presence of a well-developed collateral venous system suggested chronic obstruction and helped differentiate between thrombotic occlusion and chronic venous stenosis. Anticoagulation therapy has no effect on fixed venous fibrosis.

In this case, the combination of gastrointestinal bleeding and symptomatic SVC syndrome presented a unique problem. Along with the potential for bleeding, there is a potential for thrombosis, if heparin is used as a temporary measure to manage melena and hematochezia. In this case, and in other similar cases involving device-related venous obstruction, the anticoagulation risk balance was the greatest challenge. Anticoagulation should never be used as the sole treatment in these cases (6,7).

The extensive, and likely longstanding, venous collaterals suggest that the SVC syndrome the patient demonstrated was the outcome of a condition that was likely previously subclinical. Most patients with CIED-related venous obstruction, similar to this patient, are asymptomatic while venous collaterals are being formed, patterned, and adapted to the obstruction. Symptoms occur if venous obstruction is compounded by thrombosis, or the collaterals are insufficient. Given the condition, it is likely that a patient with chronic venous obstruction (8,9) will become symptomatic.

The patient’s management required the collaboration of numerous specialties. The presence of SVCS, along with the need to manage gastrointestinal bleeding, required the determination of the etiology of the new-onset left ventricular systolic dysfunction and the collaboration of several specialties. The presence of multiple, disparate clinical issues required a creative therapeutic and procedural approach. This case illustrates the complexity and challenges of multidisciplinary, and coordinated collaborative medicine. This is especially true for the complex cases resulting from the deployment of cardiac implanted electronic devices (CIEDs) and the resultant issues on patients (10,11).

noted was new onset heart failure with reduced ejection fraction in the range of 35-39%. The absence of significant obstructive coronary artery disease on coronary angiography, combined with the presence of pacemaker induced cardiomyopathy, raised concern. It is well established that chronic right ventricular pacing can lead to left ventricular dyssynchrony and progressive left ventricular dysfunction. Although the finding was inconclusive, it had an important effect on long-term pacing and highlighted the importance of a comprehensive electrophysiological study.

The management of symptomatic SVC obstruction associated with pacing leads has been through a combination of lead extraction and endovascular approaches. Current expert opinion and supporting literature suggest that lead extraction should be the initial approach before venous stenting in cases where the extraction is technically feasible. There is increased risk of lead entrapment as well as a detrimental effect on the chances of future lead removal and endovascular interventions after the placement of stents in the venous system. In this case, fully transvenous lead extraction was performed prior to venoplasty and stenting. This preserved the future therapeutic options.

Post-extraction, the implantation of a dual-chamber leadless pacemaker eliminates the need for additional transvenous components. Leadless pacing systems may protect the central venous system from further endothelial injury and may also prevent the development of venous obstruction. These advantages have generated interest in the use of leadless devices to mitigate transvenous-related lead issues and the need for transvenous systems extraction. ¹²

This case contains a number of teaching points. First, if collaterals are present, thrombotic occlusion should not be considered the only probable explanation for what may be described as an acute occlusion on imaging. Second, fixed venous obstruction and the presence of hematomas exclude the possibility of sufficiency of any and all anticoagulation. Third, a successful treatment most of the time requires a collaboration among various disciplines of medicine. The last point is that lead extraction and venous reconstruction, coupled with the implantation of a leadless pacemaker, resolves the symptoms and is thought to present the lowest risk of developing future venous complications associated with pacemaker implantation.

Superior vena cava (SVC) syndrome is a rare but notable syndrome associated with cardiac implantable electronic devices (CIEDs). It is primarily seen in patients with multiple transvenous leads and recurrent device interventions. Although venous stenosis is seen in many patients with pacemakers and that is often asymptomatic, it is rare to see clinically significant SVC syndrome and when it occurs, it is usually years following device implantation. Transvenous CIED leads are thought to cause chronic injury to the endothelium and, along with a host of other processes such as inflammation and fibrosis, cause progressive stenosis of the vein.¹⁻³

What is most peculiar in this case is the evolution of the diagnosis from what was thought to be acute SVC thrombosis, to chronic lead associated SVC stenosis, with possibly thrombosis superimposed. The first venous imaging was cross-sectional and showed venous thrombosis, and so venous therapy was initiated. However, the development of symptoms and the findings of venous intervention/surgery suggested a chronic obstructive process. In earlier studies, the presence of a richly developed collateral venous system suggested chronic obstruction and helped differentiate between thrombotic occlusion and chronic stenosis.⁴,⁵ Anticoagulation therapy is not effective in treating fixed fibrotic stenosis.

The coexistence of symptomatic SVC syndrome and active gastrointestinal bleeding posed a distinct challenge in this case. Along with the risk of bleeding, there is a risk of thrombosis when heparin is applied as a temporary measure to control melena and hematochezia. Balancing those risks posed a challenge in this case, as it has in similar cases of device-related venous obstruction. Anticoagulation alone should be avoided in those cases.

The extensive, and likely longstanding, venous collaterals suggest that the SVC syndrome the patient presented with was the result of a previously subclinical condition. As was the case with this patient, many of the patients with CIED-related venous obstruction are asymptomatic as venous collaterals develop and adapt to the obstruction. Symptoms become apparent when the collaterals are insufficient and when additional thrombosis venous obstruction occurs. As was the case with this patient, symptoms are likely to present in a patient with chronic venous obstruction.

The management of the patient required cooperation amongst many specialties including electrophysiology, vascular surgery, cardiology, gastroenterology and hematology. The presence of symptomatic superior vena cava syndrome (SVCS) required determination of the cause of new onset left ventricular systolic dysfunction (LVSD) as well as the management of gastrointestinal bleeding. The presence of multiple clinical issues complicated both the therapeutic and procedural choices. This case emphasizes the need for coordinated, multidisciplinary management for complex complications resulting from cardiac implanted electronic devices (CIED) and their effect on the patient.

A distinguishing feature was the new onset heart failure with reduced ejection fraction of 35-39%. The lack of significant obstructive coronary artery disease on coronary angiography raised the risk for pacemaker induced cardiomyopathy. It has been documented that chronic right ventricular (RV) pacing can lead to LV dyssynchrony and progressive LV dysfunction. Although the finding was not conclusive, it impacted the long-term pacing and emphasized the need for a detailed electrophysiological assessment.

The current treatment approach of symptomatic lead associated SVC obstruction has been a combined strategy of lead extraction and endovascular techniques. The current expert opinion and literature suggest that lead extraction should be performed prior to venous stent placement if the procedure is technically feasible. The placement of a stent in a venous segment may increase the risk of lead entrapment, and may also hinder the possibility of future lead removal and endovascular procedures. In this case, the completely transvenous lead extraction was performed prior to the venoplasty and stent placement, thereby maintaining future therapeutic options.

After extraction, the implantation of a leadless dual-chamber pacemaker has the advantage of avoiding the use of additional transvenous hardware. Leadless pacing systems may even prevent further injury to the endothelium of the central venous system and may even prevent the development of recurrent venous obstruction. There is growing interest in using leadless devices as a means of avoiding lead-related venous problems and transvenous system extraction.¹²

There are several teaching points in this case. The first is that the presence of extensive collaterals should indicate the possibility of chronic venous stenosis, even in the presence of what appears to be an acute thrombotic event on imaging studies. Second, in the presence of fixed venous obstruction and the presence of other bleeds, anticoagulation is not likely to be sufficient. Third, most often successful treatment relies on a complementary multidisciplinary approach to provide the needed obstruction. Finally, the lead extraction, venous reconstruction, and implantation of the leadless pacemaker offers immediate relief of symptoms with an approach that is considered to have the least potential for recurrent pacemaker-associated venous complications.

In patients who undergo repeated lead placements and cardiac device interventions, Superior vena cava (SVC) syndrome is a rare, but emergent, phenomenon caused by the presence of cardiac electronic implantable devices (CIEDs). It is known that the majority of patients with pacemakers experience asymptomatic venous pacemaker-related stenosis, and clinically significant SVC syndrome is known to occur years following device implantation. It is hypothesized that SVC syndrome is caused by chronic venous lead injury that promotes and initiates inflammation, venous fibrosis, and hyperplasia, ultimately causing venous stenosis.¹⁻³

This case illustrates a unique diagnostic progression from presumed acute venous thrombosis to chronic lead-related SVC syndrome with superimposed venous thrombi. Cross-sectional imaging, in this case, was used to visualize venous thrombosis, and as a result, venous thrombotic therapy was initiated. Symptoms that progressed during the case along with the development of venous collaterals and the findings of the surgical intervention, indicated the presence of chronic SVC obstruction. There have been multiple studies that have indicated that the presence of well-defined venous collaterals indicate chronic venous obstruction and help to differentiate between chronic venous stenosis and acute venous obstruction.⁴,⁵ From a clinical perspective, this differentiation is important as the presence of chronic venous injury will not respond to thrombotic therapy, and therefore, the injury will remain.

The combined presence of symptomatic SVC syndrome and gastrointestinal bleeding presented a unique challenge in this case. Anticoagulation is considered a critical part of the management strategy in the setting of acute thrombus but plays a more ambiguous role in the context of chronic device-related venous stenosis. Recurrent melena and hematochezia required the temporary suspension of heparin, and this advanced the already difficult challenge of tailoring the thrombotic and bleeding risk. Device-associated venous obstructions have presented the same challenges, highlighting the need for therapeutic approaches that extend beyond the use of anticoagulants.6

The presence of extensive collateral circulation in this case, despite a relatively short symptomatic history, supports the hypothesis that clinically evident SVC syndrome can be the decompensation of a subclinical process of some duration. Numerous patients with CIED-related venous obstructions remain asymptomatic because collateral pathways develop gradually and compensate for impaired venous return. Symptoms typically develop when collateral capacity is exceeded or when superimposed thrombosis further compromises venous drainage.4,7 The same probable mechanism explains the patient's presentation, given the evidence of chronic venous disease.

In addition to symptomatic SVC syndrome, this patient presented additional challenges for management on account of gastrointestinal bleeding and newly diagnosed left ventricular systolic dysfunction. Competing clinical challenges further complicated timing of intervention and therapeutic choices. This case exemplifies the complexity of challenges faced when managing SVC related complications for patients with implanted devices and the need for multiple medical specialties to provide optimum healthcare for the patient.⁸

A unique feature of this case related to the newly diagnosed heart failure with reduced ejection fraction (35 - 39%). Because there was no evidence of significant coronary artery disease on angiography, this raised the possibility of pacemaker induced cardiomyopathy. The chronic pacing of the right ventricle may have resulted in dyssynchrony and caused progressively left ventricular failure, particularly with a high pacing burden. In the absence of a definitive cause, it became the basis for long-term pacing and the comprehensive electrophysiology perspective.

The current management for symptomatic obstruction of the superior vena cava (SVC) caused by lead materials is combined lead extraction with an endovascular intervention. The current consensus among experts indicates that lead extraction should be performed if possible prior to placement of a venous stent. Stenting of the vena cava with retained leads can pose risk of lead entrapment, complicate extraction of the leads, and restrict venous access in the future. In this case, the complete extraction of the leads was performed prior to venoplasty and the placement of the stents.

After lead extraction, implantation of a leadless dual-chamber pacemaker was an additional benefit to avoiding the placement of new transvenous circuitry. Leadless pacing systems do not damage the endothelial lining of the central venous system and may even reduce the risk of obstructive venous syndrome. Recent studies have shown that leadless pacing devices may be a viable option for patients with obstructive lead-related complications and patients with implanted transvenous devices that have been removed.¹²

There are multiple lessons to be learned from this case. First, if there is the presence of extensive collateral circulation, there is a high likelihood of chronic venous stenosis, even if the imaging shows findings consistent with acute thrombosis. Second, for fixed fibrotic obstruction, anticoagulation may be less effective, especially if there is a high risk of bleeding. Third, to be successful, treatment may also require a multidisciplinary approach. One of the lessons learned from this case is that in the treatment of device-related venous complications, lead extraction, venous reconstruction, and leadless pacemaker implantation is a valid, modern approach to provide long-lasting relief to the patient.

The Patient Health Questionnaire-9 (PHQ-9) will be the instrument to assess level of depression in this study. The PHQ-9 is a 9-item instrument in which respondents rate the frequency (0: not at all to 3: nearly every day) of each symptom. Total scores can range from 0 to 27. Based on total scores, depression can be classified as having a range from no depression (0), minimal (0-4), mild (5-9), moderate (10-14), moderate severe (15-19), and severe (20-27). An aggregate score of 10 or higher is indicative of clinically significant depression.

The Generalized Anxiety Disorder-7 (GAD-7) scale will also be used to assess anxiety. The GAD-7 is a 7-item scale with scoring from 0 (not at all) to 3 (nearly every day). Total scores can range from 0 to 21. The severity of anxiety may be classified as minimal (0–4), mild (5–9), moderate (10–14), and severe (15–21). A score of 10 or more will be considered as clinically significant anxiety.

Statistical Package for Social Sciences (SPSS) version 26 will be used for data entry and analysis. Age, anxiety and depression scores will have their distributions assessed using the Shapiro-Wilk test. For normally distributed scores, results will be reported as mean ± standard deviation. For not normally distributed scores, results will be reported as median and interquartile range. Variables such as gender, marital status, residency year, sleep hours, working hours, social support and financial and anxiety/depression stress will be assessed and reported in frequencies and percentages.

The percentage of the study population with anxiety and depression will be reported. Relationships between the proposed categories and anxiety and depression will be assessed using the Chi-square test and Fisher’s exact test as appropriate. For proposed categories with score data, when score data is normally distributed, the Independent Sample t-test and One-Way ANOVA will be used. For not normally distributed score data the Mann-Whitney U test and the Kruskal-Wallis test will be used. Multi-variable Binary Logistic regression will be used to determine anxiety and depression’s independent risk factors and to assess the effect of the proposed categories. A p-value of 0.05 will be the threshold of statistical significance.

Once the College of Physicians and Surgeons Pakistan (CPSP) Research Evaluation Unit and the Institutional Review Board (IRB) of the study hospital approve the synopsis, data collection will commence. Eligible pediatric residents will be contacted in the Department of Pediatrics. The aims and methods of the study will be shared, and written informed consent will be secured prior to data collection. A structured proforma will be used to collect data on demographic and work-related factors, psychosocial factors, anxiety and depression using the Generalized Anxiety Disorder-7 (GAD-7) scale and the Patient Health Questionnaire-9 (PHQ-9), respectively. Data will be collected via self-administered questionnaires and will be as informative as possible while minimizing bias using validated instruments. Assumptions will be recorded and adjusted for in the final analysis. They include age, gender, marital status, work-related factors, sleep, social and financial stress, exposure to patient death and/or night duty, and shifts. All information collected will be confidential.

Following the endorsement of the synopsis from the CPSP Research Evaluation Unit and the Institutional Review Board (IRB) of the study hospital, data gathering will commence. Pediatric residents within the inclusion criteria will be identified in the department of pediatrics. Study aims and objectives along with procedures will be clarified, and participants will be asked to provide their written informed consent to participate. A structured data collection proforma will capture participants' demographics, work-related and psychosocial factors, the GAD-7 as a measure of anxiety, and the PHQ-9 to measure depression. Self-administered questionnaires will be utilized to capture data. To reduce information bias, questionnaires will be validated and participants will be allowed to complete the questionnaires in an anonymous format. Age, gender, marital status, residency year, duty hours, night shifts, sleep duration, financial distress, social support, and exposure to patient death will be noted as potential confounding variables and will be controlled for during data analysis. All information will be collected and retained in a manner to preserve participants' privacy.

Pediatric resident trainees face unique stressors related to prolonged duty hours, disrupted sleep patterns due to night duties, emotional stress from working with critically ill children, and pressure from demanding academic workload/s. These stressors predispose residents to higher levels of anxiety and depression. Psychological distress may have a negative impact on residents’ well-being and affect their clinical practice and the quality of care they provide to their patients. While the high incidence of anxiety and depression among resident physicians has been well documented in many international publications, there is a paucity of published data on anxiety and depression among pediatric resident physicians. Hence, this study has been developed to establish the incidence of anxiety and depression, and the associated risk factors, among pediatric trainees, to provide a basis to develop mental health support and wellness programs of a specific nature.