Molecular insights into salpingitis-induced infertility and ectopic pregnancy: pathogenesis, biomarkers, and translational perspectives.

Salpingitis induces infertility, since it affects the structural and functional integrity of the fallopian tubes, via which gametes are carried, fertilized, and the early embryo grows. Fibrosis and scarring constrict or block the lumen of the tube, and the oocyte and the sperm are not able to come in contact. When fertilization occurs, decreased ciliary movement and abnormal tubal secretions make it difficult to allow the embryo to migrate toward the uterus and limit implantation potential [ 36 ]. The microenvironment of fallopian tubes is also altered by chronic inflammation in a manner that is deleterious to reproduction. High cytokines and chemokines establish an unfavorable environment for gametes and embryos, lowering their viability. Moreover, immune cell activities refer to oxidative stress that damages not only tubal epithelium but also gametes, which are all causes of subfertility. Even though direct gamete or embryo toxicity has not been well established, a number of studies have indicated that the reduced implantation rates in ART in women with hydrosalpinx or chronic salpingitis are mainly due to retrograde discharge of inflammatory tubal fluid into the uterine cavity. This fluid establishes a biochemical barrier between the endometrium and embryo, which prevents implantation and not direct cytotoxicity [ 45 ]. Notably, the association between salpingitis and infertility is not confined within the natural conception, but also to assisted reproductive outcomes. Diseases like hydrosalpinx which is a common follow-up of chronic salpingitis cause the inflammatory fluid to leak toxic material into the uterine cavity making implantation of embryo during in vitro fertility (IVF) impossible [ 12 ]. Figure  13 shows how likely each damage to be cause is in case of Salpingitis. Fig. 13 Proportion of clinical consequences associated with salpingitis Proportion of clinical consequences associated with salpingitis Salpingitis derails the sensitive balance of the fallopian tubes, which interferes with the communication between sperm and oocyte. Inflammation changes secretions of the tubes that are used to control sperm capacitation and survival and decrease the chances of success of the fertilization process. Injury to the epithelial surface and ciliary paralysis further hamper the delivery of gametes to the ideal site of fertilization, which worsens the impact of changed tubal physiology. Besides this, gametes’ quality is compromised by the production of inflammatory mediators and oxidative stress in the process of salpingitis. Table 3 explains long-term outcomes by PID events. Reactive oxygen species can damage the sperm DNA and reduce the sperm motility, and oocytes subjected to an inflammatory microenvironment might experience reduced developmental competence. Collectively, these consequences undermine the efficiency of fertilization [ 12 ]. Table 3 Long-term outcomes by number of PID/salpingitis events Number of episodes Infertility (%) Ectopic pregnancy (%) Chronic pelvic pain (%) 0 (baseline) 0.9 1.3 5 1 12 8 25 2 25 15 30  ≥ 3 50 28 40 The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list Long-term outcomes by number of PID/salpingitis events The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list

Most cases of salpingitis are ascending genital tract infections, the most common being sexually transmitted. Chlamydia trachomatis is also known to be the most prevalent infectious agent in the globe and is characterized by its capacity to induce chronic and, in most cases, asymptomatic infections that slowly destroy the fallopian tubes [ 16 ]. Another significant pathogen is Neisseria gonorrhoeae , which is usually linked to acute and severe inflammatory events that may easily affect the integrity of the tubes [ 17 ]. There are some mechanistic data (summarized in this section) that were obtained in animal models (avian, bovine, and murine). These results offer supportive information, but probably do not reflect physiology in human tubes. Along with these classical agents, there is a wide assortment of microorganisms that are known to contribute to salpingitis. Mycoplasma genitalium , anaerobic bacteria, and Ureaplasma urealyticum have increasingly been implicated, usually in the form of polymicrobial associations that increase inflammation. Table 1 explains the pathogens and their clinical trials. The occurrence of the various pathogens not only enhances the inflammatory response but also makes treatment quite complicated, especially in areas that do not have many diagnostic microbiology facilities [ 18 ]. Table 1 Pathogens and their clinical impact Pathogen Estimated contribution to salpingitis (%) Key features Reproductive risks Chlamydia trachomatis 45–55 Often asymptomatic, chronic, persistent 30–40% infertility risk if untreated; 6 × ectopic pregnancy risk Neisseria gonorrhoeae 15–25 Acute, symptomatic, rapid tubal injury Moderate infertility risk; high acute damage Mycoplasma genitalium 10–15 Frequent co-infection; rising detection 2–3 × increased infertility risk Ureaplasma urealyticum 5–10 Opportunistic, often polymicrobial Low–moderate infertility risk Anaerobic bacteria 5–10 Associated with bacterial vaginosis Chronic inflammation and scarring Viral co-factors (HPV/HSV) 3–5 Indirect role, enhanced bacterial persistence Low direct risk The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list Pathogens and their clinical impact The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list There is also new evidence that viral infections and vaginal microbiome disruptions could also determine salpingitis susceptibility. The human papillomavirus and herpes simplex virus have been suggested as co-factors in tubal inflammation, although their roles are less clear. Alterations in the defensive homeostasis of commensal flora, especially loss of Lactobac illus supremacy, can also predispose women to opportunistic infections that can enter the fallopian tubes [ 19 ]. Figure  5 shows the contribution of infectious agents to salpingitis and the reproductive risk associated with them. Fig. 5 Contribution of infectious agents to salpingitis and the associated reproductive risk Contribution of infectious agents to salpingitis and the associated reproductive risk Even though infections are the most common cause of salpingitis, there are also non-infectious causes of the disease and its developments. Pathogens or induction of sterile inflammation damaging the tubal tissue can be caused by surgical procedures including hysteroscopy, dilation and curettage, or previous tubal surgeries. Figure  6 explains the vaginal infection within the female body [ 20 ]. Likewise, salpingitis has been linked with the use of intrauterine devices (IUDs), especially in those cases when they are placed under non-sterile conditions or in patients with unidentified infections of the genital tract [ 21 ]. Fig. 6 Immune response components involved in salpingitis pathophysiology Immune response components involved in salpingitis pathophysiology The second important risk factor is endometriosis, as local inflammatory responses that are comparable to salpingitis may be induced by ectopic endometrial tissue in or surrounding the fallopian tubes, as shown in Fig.  7 [ 19 ]. Autoimmune mechanisms have also been proposed where an abnormal immunity may be keeping the tubes inflamed despite the absence of active infection. These processes accentuate the fact that salpingitis is not an exclusive by-product of pathogens, but can also be a result of complicated host-specific factors. Fig. 7 Endometriosis overview Endometriosis overview The vulnerability is additionally affected by lifestyle and sociodemographic factors. The risk of being infected with salpingitis, especially an infectious process or sterile, is increased by early sexual initiation, sexual partners, lack of access to reproductive health services, and low socioeconomic status. The combination of these non-infectious causes and risk factors indicates that the disease is multifactorial, which necessitates multifactorial prevention strategies that will incorporate both biological and social determinants. Salpingitis is frequently initiated as an acute inflammatory event caused by infection or obstruction of the fallopian tubes. At early stages, the infiltration of neutrophils, edema, and hyperemia are the features of the condition, leading to complications such as pelvic pain and fever. Acute salpingitis can be cured without permanent injury and may be self-limiting, but when the disease is not treated or treated late, it often predisposes the individual to chronic disease [ 22 ]. As the disease advances to chronic salpingitis, the immune response changes to persistent lymphocyte, plasma cell, and macrophage infiltration. This is a sustained inflammation, which results in tissue remodeling, fibrosis, and scarring of the tubal epithelium, which alters the structure and function. Ciliary paralysis and lumen constriction or blockage greatly affect the transport of gametes and embryos and cause reproductive complications. Chronic salpingitis can be asymptomatic and is thus hard to diagnose until infertility or ectopic pregnancy develops. Recurring events of acute inflammation also facilitate additional destruction of the tubes, which supports the develpment of chronic malfunction. This acute–chronic shift indicates the significance of early diagnosis and treatmen,t since prevention of progression is essential to maintain reproductive potential [ 23 ]. Figure  8 shows the increasing reproductive morbidity with recurrent events of salpingitis. Fig. 8 Increasing reproductive morbidity with recurrent events of salpingitis Increasing reproductive morbidity with recurrent events of salpingitis

The pathogenesis of salpingitis is centered on the inflammatory process, and cytokines and chemokines play an important role in mediating tissue damage. Infections activate the release of interleukins (IL-1β, IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), and other mediators that come to the fallopian tubes to recruit immune cells. These indicators augment local inflammation, disturb epithelial homeostasis, and damage tubal integrity and activity [ 28 ]. Further structural and functional damage is caused by immune cell infiltration. Neutrophils and macrophages release extracellular reactive oxygen species and proteolytic enzymes which play a role in epithelial injury and ciliary dysfunction. Chronic inflammation is sustained in the long term by lymphocyte and plasma cell penetration which enables fibrosis and scarring. Although these changes are initially defensive, they end up remodeling the tubal microenvironment in a manner that is harmful to reproductive health. Table 2 shows the cytokine levels in patients diagnosed with salpingitis. Newer evidence also indicates that certain cytokine axes play a crucial role in the maintenance of chronic salpingitis. Increased expression of IL-1β, TNF-α, and IFN-γ is associated with sustained epithelial injury, macrophage recruitment, and oxidative stress enhancement. These mediators not only exacerbate fibrosis, but also upset local immune tolerance, supporting auto-reactivity against tubal epithelial antigens. It can be postulated that disordered Th1/Th17 responses contribute to maintaining an inflammatory state, indicating that chronic tubal inflammation is not only infectious, but also an immunological autoimmune condition. Table 2 Cytokines elevated in salpingitis Cytokine/chemokine Control levels (pg/mL) Salpingitis levels (pg/mL) Clinical role IL-1β  ~ 20  ~ 80 Promotes tubal inflammation and scarring IL-6  ~ 15  ~ 60 Drives systemic inflammation, fever IL-8 (CXCL8)  ~ 25  ~ 120 Strong neutrophil recruitment, tissue damage TNF-α  ~ 10  ~ 45 Cytotoxic, induces apoptosis, fibrosis CCL5 (RANTES)  ~ 12  ~ 55 Sustains chronic inflammation, immune infiltration The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list Cytokines elevated in salpingitis The presented values were obtained by synthesis across several peer-reviewed works and reflect reported ranges of values instead of an individual dataset. All details are mentioned in the reference list CXCL8 and CCL5 are chemokines that recruit additional immune cells and stabilize the process of chronic inflammation. At the same time, the role of inappropriate regulatory T-cell functions and changes in local immune tolerance is associated with prolonged tissue destruction. Altogether, these inflammatory and immune pathways indicate the multifaceted nature of host defense and collateral tissue destruction that is the basis of the long-term reproductive implications of salpingitis [ 29 ]. Figure  11 shows a comparison of cytokine expression in women with salpingitis versus healthy controls. Fig. 11 Comparative cytokine expression in salpingitis versus healthy controls Comparative cytokine expression in salpingitis versus healthy controls The pathways of immune system escape and inducement of tissue destruction in the tubes are fundamental to the persistence and severity of salpingitis, since microorganisms apply dedicated pathways of immune clearance escape. An example is Chlamydia trachomatis , as illustrated in Fig.  12 , which causes apoptosis of the epithelial cells and host gene expression changes, allowing chronic infection with only a few symptoms. Neisseria gonorrhoeae attaches to the epithelial cells with the help of pili and outer membrane proteins to enable entry and persistent inflammation. These measures enable pathogens to survive as they cause progressive damage [ 30 ]. Fig. 12 Pathogenesis of Chlamydia trachomatis Pathogenesis of Chlamydia trachomatis At the molecular scale, Toll-like receptor and other pattern recognition receptors of epithelial and immune cells are triggered by microbial components including lipopolysaccharides and heat-shock proteins [ 31 ]. The outcome of this stimulation is the downstream signal cascade, i.e., NF-kB and MAPK (mitogen-activated protein kinase (MAPK) signaling is a key intracellular pathway regulating inflammation, apoptosis, and fibrosis within tubal epithelial cells) signatures, which lead to the release of prolonged cytokines causing chronic inflammation. Not only does such signaling add to tissue damage, but it also maintains the immune activation/pathogen survival cycle [ 32 ]. Also, pathogens may be able to generate control over the responses of the host immune system. Chlamydia impacts antigen presentation and promotes anti-apoptotic signals in infected cells, whereas Mycoplasma genitalium alters the integrity of the epithelial barrier, which increases co-infection. Such complicated interactions highlight the point that salpingitis is never just an outcome of infection, but a complex interplay of molecules in battle where the pathogens face off with the host and at the end the process determines the reproductive outcome [ 33 ]. Besides microbial influences, epigenetic changes are being recognized as major modulators of tubal pathology. Research has shown that chronic infection causes an increase in hypermethylation levels of genes regulating epithelial regeneration and ciliary structure, which inhibits the ability to repair tissue. Concurrently, microRNAs including miR-223, miR-155, and miR-21 are induced, promoting repression of anti-fibrotic signaling and increased collagen production. These inheritable but reversible changes at the molecular level can account for tubal dysfunction rebounding after pathogens have been removed, and may provide fertile new ground for the discovery of biomarkers or therapeutics [ 32 ].

Salpingitis leads to long-term severe structural damage of the fallopian tubes, which is greatly attributed to the persistence of inflammation and remodeling of tissues. Repeated infections increase fibrosis, adhesions, and wall thickening of the tubal wall, which constricts or obstructs the lumen. These tissue changes upset the delicate anatomy of the mucosal folds, creating mechanical barriers to gamete and embryo migration. These changes ultimately make the tubes permanently dysfunctional and infertile [ 24 ]. Besides structural damage, salpingitis eliminates the functional integrity of the tubal epithelium. Normal and diseased fallopian tubes are well illustrated in Fig.  9 . The ciliated cells involved in gamete and embryo transport lose their ciliary density and undergo reduced beat frequency under chronic inflammatory stress. At the same time, secretory cells depict elevated activity, which breaks the biochemical environment that is required to undergo fertilization and early embryo development. All these functional impairments reduce the ability of the fallopian tube to enable conception [ 25 ]. In several parts of this review, fibrosis, ciliary dysfunction, and chronic inflammatory remodeling continually appear as the underlying processes that result in salpingitis-related infertility and ectopic pregnancy. These common lines of investigation are considered here as one, since doing so avoids repetition, which would otherwise be the case in each section. Fig. 9 Normal vs. diseased fallopian tube Normal vs. diseased fallopian tube Reproductive risk is enhanced by the interaction between structural and functional changes. These two mechanisms of fibrotic scarring and cytoskeleton loss together contribute to blocking the movement of gametes, which enhances the risk of infertility or ectopic implantation. Notably, the mentioned changes can be observed even after active infection is resolved, which highlights the idea that the impact of salpingitis has many implications well beyond the acute period [ 26 ]. The structural and functional damage of salpingitis directly disrupts fertilization. Reduced or blocked lumens prevent the interaction of the sperm and oocyte, and impaired secretory functions interfere with the optimal microenvironment needed by gametes to survive. Although fertilization may take place, the disturbed and altered biochemical milieu would limit the embryo quality and viability, decreasing the chances of a successful conception. Another significant effect of salpingitis is defective embryo transport. Destruction of ciliary movement, fibrosis, and adhesions slow or halt embryo movement along the tube. This latency raises the chances of tubal implantation, and hence the interconnection of salpingitis to ectopic pregnancy. Partially blocked cases can either permit fertilization and inhibit adequate transfer into the uterus or permit fertilization but inhibit full contagious transfer, establishing a high-risk environment of reproductive failure [ 27 ]. These effects are clinically presented in the form of subfertility, frequent pregnancy loss, or ectopic pregnancy. Women with a history of chronic salpingitis normally have lower chances of natural conception and poor prognoses regardless of assisted reproductive technologies. In this way, the interference with fertilization and transportation of the embryo is the manifestation of structural and functional damage to tubes, which demonstrates the decisive importance of salpingitis in the pathology of childbirth. Figure  10 shows a simplified molecular pathway of tubal damage in salpingitis. Fig. 10 Simplified molecular pathway of tubal damage in salpingitis Simplified molecular pathway of tubal damage in salpingitis

The reproductive damage that is caused by salpingitis happens via inflammatory signaling. Tubal activates pathogens with the help of TLRs and other pattern recognition receptors on tubal epithelial and immune cells with cascades mediated by NF-kB and MAPK. This stimulation triggers the prolonged release of cytokines and chemokines like IL-1β, IL-6, TNF-α that extend the inflammatory process and enhance tissue damage [ 37 ]. These pathways cause disruption of tubal homeostasis through the enhancement of immune cell infiltration, oxidative stress, and epithelial cell apoptosis. The persistent activation of NF-kB assists in stimulating fibrosis and scarring, but MAPK activation enhances the synthesis of matrix metalloproteinases (MMPs) which degrade the extracellular matrix. Together, these effects cause weakening of the structural and functional integrity of the fallopian tubes [ 37 , 38 ]. In addition to local tissue destruction, chronic inflammatory signaling changes the viability of gametes and embryos. Oxidative stress caused by the action of cytokines leads to dysfunction of sperm motility, oocyte impairment, and abnormal development of embryos. This shows the role of inflammatory processes as molecular bridges between salpingitis and infertility, as well as ectopic pregnancy, and thus as the central biomarker discovery and therapeutic intervention target [ 39 ]. Figure  16 shows the distribution of biomarker categories investigated in salpingitis research. Fig. 16 Distribution of biomarker categories investigated in salpingitis research Distribution of biomarker categories investigated in salpingitis research Salpingitis is stress that is triggered by oxidation when the immune system exerts excess production of reactive oxygen species (ROS) exceeding antioxidants, causing damage to the tubal epithelial and ciliary structures. Overproduction of ROS encourages lipid peroxidation, protein alteration, and DNA damage and leads to epithelial cell apoptosis and necrosis. These alterations undermine the structure of tubes and interfere with the harmonious processes in the delivery of gametes and embryos [ 40 ]. In addition to local tissue destruction, oxidative stress directly affects the reproductive cells. Sperm which are subjected to ROS become less motile and their DNA is fragmented, whereas oocytes lose their developmental competence. Such environments are characterized by poor survival or early arrest of embryos. Therefore, oxidative stress is one of the focal points between the salpingitis and the negative reproductive outcomes, and therefore is a potential target of therapeutic and diagnostic approaches [ 40 , 41 ]. Figure  17 shows a radar chart comparing the diagnostic characteristics of different biomarker categories used in salpingitis research. Fig. 17 Comparative diagnostic utility of biomarker categories in salpingitis Comparative diagnostic utility of biomarker categories in salpingitis Imaging is important in identifying the structural damage caused by salpingitis and in assessing tubal function. Transvaginal ultrasound (TVUS) and hysterosalpingo-contrast sonography (HyCoSy) are minimally invasive methods for the detection of hydrosalpinx, adhesions, and tubal dilation. An alternative to functional assessment to assess patency is hysterosalpingography (HSG), which is not comfortable and less specific. The gold standard is laparoscopy due to the visualization of the pathology. However, its invasive nature limits the use of this to more advanced or less certain cases [ 42 ]. Molecular diagnostics is a complementary technology to imaging in the detection of pathogens and host response markers. The etiology is still confirmed with nucleic acid amplification tests (NAATs) of Chlamydia trachomatis and Neisseria gonorrhoeae . New procedures such as multiplex PCR and microbiome sequencing can be useful in the detection of co-infections and microbial dysbiosis. In biomarker discovery, including cytokine panels, and microRNAs are biomarkers that are being prioritized to detect subclinical or irreversible injury. These tools have the potential to be improved with imaging, but both the validation and cost-effectiveness are a problem [ 43 ]. Figure  18 shows the rise of different diagnoses over the last 25 years. Fig. 18 Trends in diagnostic modality sensitivity/uptake for tubal disease (2000–2025) Trends in diagnostic modality sensitivity/uptake for tubal disease (2000–2025) To improve early diagnosis, the integration of new technologies, including multiplex PCR (mPCR), next-generation sequencing (NGS), and AI-based image analysis, is increasingly emerging. On the one hand, metagenomic sequencing provides a way to identify pathogenic and dysbiotic microbial communities at multiple pathogens’ levels OMICS level simultaneously; on the other hand, AI-assisted ultrasonography and radiomics are able to classify changes of tubal structure automatically with high sensitivity. The integration of molecular diagnostics and computational speciation may reshape early diagnosis of subclinical salpingitis and enable personalized therapeutic strategies [ 42 ].

Although there has been an advancement in the knowledge of salpingitis, there are significant obstacles in the diagnosis and early diagnosis of the disease. Numerous cases are subclinical or asymptomatic, which results in late presentation with infertility or ectopic pregnancy. Laparoscopy is the gold standard and is invasive and inappropriate for routine use, whereas imaging techniques are not sensitive enough to identify early or subtle changes in the tubes. Currently, there is no validated biomarker panel, which is an important gap in cost-effective and non-invasive screening. Such restrictions slow down the early intervention and deteriorate the future reproductive prognosis [ 48 ]. Heterogeneous definitions, lack of longitudinal studies, and small sample sizes are research limitations that restrict comparison and meta-analysis of studies on salpingitis. The examination of the fallopian tube tissue with direct methods is both ethically and practically challenging, and existing animal models do not reflect the anatomy and development of chronic diseases of the human body. Molecular and microbiome research is also confronted with the problem of contamination, sampling bias, and absence of reproducibility, which has caused difficulty in reproducibility [ 49 ]. Management is challenged by therapeutic and public health issues, since antibiotics provide treatment to acute infection, but not typically long-term consequences. Surgical and assisted reproductive therapy is expensive, unpredictably good, and not available to all patients. Increasing antimicrobial resistance also makes treatment more difficult, particularly in resource-constrained areas where surveillance is low [ 50 ].

Salpingitis is a major issue in reproductive medicine and has long-term implications on fertility and maternal well-being throughout the world. Although there have been considerable developments in the knowledge of its microbial and immunological pathogenesis, the condition is frequently asymptomatic and does not receive timely diagnosis. The existing diagnostic modalities, on one hand, are either invasive or lack sensitivity and, on the other hand, therapeutic interventions, though effective in treating acute infection, are not always effective in preventing tubal damage in the long term. Such gaps highlight the importance of new approaches that have the potential to bridge basic science and clinical use [ 1 , 2 ]. The heterogeneity in study design, small cohorts, and accessibility to ethically available human tissues have somewhat hampered research progress. Although there are some promising pathways and promising biomarkers that have been identified in literature on both molecular and microbiome, they are yet to be translated into validated and non-invasive diagnostic tools. Similarly, mechanical knowledge is limited by the lack of preclinical models, which recapitulate human physiology of the fallopian tube. The mitigation of these shortcomings will be a key to the progress in the field [ 1 , 49 ]. The future directions should be aimed at integrating molecular diagnostics and imaging and clinical algorithms with improved antimicrobial stewardship development and universal burden of resistance. Equal access to reproductive health services, especially in low-resource countries, is also critical in lowering late-stage disease burden. Through scientific innovation and strong public health measures, the reproductive implications of salpingitis can be reduced and greatly benefit women who have it [ 44 ].

Salpingitis is a cause of ectopic pregnancy, since it changes the structural and functional integrity of fallopian tubes. The inflammatory injury causes scarring, adhesions, and partial obstructions that interfere with the transportation of the embryo to the uterus. Simultaneously, the cilia paralysis and impeded smooth muscle contractions slow down the embryo’s mobility, increasing the opportunity for tubal implantation [ 34 ]. Abnormal implantation is also conducive to the presence of the inflammatory environment. High levels of cytokines and chemokines provide conditions that might facilitate premature trophoblast attachment. The tubal epithelium, in contrast to the uterus, is not implantable, but the receptivity of the tubal epithelium is changed by exposure of the extracellular matrix to chronic salpingitis. These differences contain molecular anchors that stimulate attachment of ectopic embryos, as shown in Fig.  14 [ 35 ]. Fig. 14 Intersection of prevention strategies for salpingitis Intersection of prevention strategies for salpingitis Constant immune response is another risk factor, as it undermines embryo survival and destroys tubal tissue. The abnormal environment produced by oxidative stress, immune infiltration, and tissue remodeling increases the likelihood of implantation outside the uterus. All these processes illustrate how salpingitis causes the tubes to change into a site of implantation that is pathological. Women with previous salpingitis have continued reproductive problems despite the acute infection being healed. Recurrent ectopic pregnancy is not ruled out because of permanent scarring of the tubes and defective transport systems. The effect of such is not only a danger to maternal health, but also diminishes the chances of having a safe intrauterine pregnancy in future reproductive efforts. There are also long-term implications that spread to fertility outcomes. Chronic tubal factor infertility develops in many women and restricts natural conception and the use of assisted reproductive technologies including IVF. Nevertheless, the existence of defective or fluid-filled tubes, such as hydrosalpinx, may have a detrimental impact on fertilization or result in premature loss of pregnancy. These complications render the reproductive health management of salpingitis quite complicated [ 36 ]. In addition to infertility, recurrent inflammation and ectopic pregnancies are also a psychological and emotional weight that may exacerbate the physical issues. The fear of constant loss or low fertility might have a very great effect on the quality of life. Fig.  15 shows the distribution of treatment strategies for salpingitis. All these risks, in the long term, demonstrate the importance of timely diagnosis, quality treatment, and specialized counseling of childbearing women with a salpingitis history [ 44 ]. Fig. 15 Distribution of treatment strategies for salpingitis Distribution of treatment strategies for salpingitis

Salpingitis is a widespread problem of reproductive health, and its incidence varies significantly across geography due to the variation in healthcare, diagnostic, and sexual health practices [ 6 ]. Chlamydia trachomatis and Neisseria gonorrhoeae are the most prevalent causes of salpingitis in women of childbearing age with sexually transmitted diseases. In developed countries, prevalence has dropped as a result of enhanced screening and antibiotic therapy; however, there is still the concealed burden of disease as a result of asymptomatic infections [ 2 , 7 ]. In contrast, the prevalence and complication rates remain higher in third world countries, which can be explained by the lack of access to preventive services and late-stage treatment. Poor awareness and insufficient screening programs in these areas contribute to the persistance of infections, which advance to chronic salpingitis with chronic effects on reproductive life. Cultural and socioeconomic factors contribute to further regional inequalities and sexual health behaviors and treatment-seeking practices [ 8 ]. Salpingitis is commonly underestimated in its actual prevalence, since many are subclinical and therefore detected only when infertility or ectopic pregnancy occurs. The overview of vaginal infection is illustrated in Fig.  1 . The epidemiological reports indicate a high incidence of global tube factor infertility attributed to untreated or recurrent salpingitis. This under-identification demonstrates the urgent necessity of more sensitive methods of diagnostics and conventional surveillance systems [ 9 ]. Fig. 1 Anatomical context of ascending genital tract infections leading to salpingitis Anatomical context of ascending genital tract infections leading to salpingitis Salpingitis stands out as a prominent factor in female infertility, particularly in the context of tubal factor infertility. The chronic or recurrent inflammation of the tubal surfaces leads to disruption of the epithelial cell layer in the lumen, ciliary dysfunction, and fibrosis, all of which obstruct normal movement of gametes and embryos, as given in Fig.  2 . Epidemiologic estimates suggest that infertility in as much as one-third of women in the world may be the outcome of one or more stages of pelvic inflammatory disease, with salpingitis as a key factor [ 10 ]. Fig. 2 Salpingitis and ectopic pregnancy Salpingitis and ectopic pregnancy It is particularly strong in women with untreated or recurrent infections, in which cumulative damage to the tubes greatly reduces the likelihood of natural conception [ 11 ]. The tubal environment, even in the case of conception, could also be unfavorable, thereby compromising fertilization or an earlier developing embryo, diminishing reproductive success further. Female fertility preservation is illustrated in Fig.  3 . This correlation is especially observed in areas with low access to healthcare resources, which slows the therapeutic process and predisposes individuals to secondary tubal injury [ 12 ]. Notably, salpingitis does not only lower fertility, but also complicates assisted reproductive technologies (ART). Fig. 3 Clinical pathways linking salpingitis with fertility outcomes Clinical pathways linking salpingitis with fertility outcomes Women with previously damaged tubes have been found to have low success rates in in vitro fertilization (IVF) in comparison to women who do not have that history. Implantation and pregnancy outcomes can also be further harmed by the presence of hydrosalpinx (hydrosalpinx refers to the fluid-filled distension of the fallopian tube caused by chronic inflammatory obstruction), which is also a frequent sequela of chronic salpingitis. Therefore, the epidemiological connection between salpingitis and infertility leads to both biological and clinical treatment issues [ 13 ]. Although methods of fertility preservation like oocyte cryopreservation have become more and more common, it is not effective in cases where the integrity of the tubes has been severely affected by chronic salpingitis. Hence, averting inflammatory damage is still more important than fertility preservation strategies in reducing the risk of infertility. Salpingitis has been closely linked to a high risk of ectopic pregnancy; this is mainly because of the structural and functional injury caused to the fallopian tubes. Scarring, adhesions, and dysfunction of the cilia caused by inflammation disrupt the normal fertilized ovum transportation, forcing its implantation in the tube instead of the uterine cavity, as shown in Fig.  4 . Epidemiological research studies have repeatedly indicated that women having a history of pelvic inflammatory diseases or salpingitis are at a two- to sixfold increased risk of developing ectopic pregnancy as compared to unaffected women. Fig. 4 Chronic inflammation leading to fibrosis and epithelial transformation in salpingitis-induced tubal pathology Chronic inflammation leading to fibrosis and epithelial transformation in salpingitis-induced tubal pathology There is also an augmented risk in cases of frequently recurrent or untreated infections, whereby incurring fibrosis and tubal distortion gradually decrease the likelihood of implantation. Hydrosalpinx and partial tubal obstruction, which are typical consequences of chronic salpingitis, provide the circumstances in which the embryo is trapped in the tube. Such results are especially prevalent in areas with limited access to healthcare, where the infections cause tubal pathology in the long run [ 14 ]. Chronic salpingitis-associated fibrosis has been implicated in epithelial transformation that may predispose to tubal and ovarian malignancies, consistent with recent histopathologic evidence [ 5 , 28 , 30 ]. Ectopic pregnancies resulting from salpingitis have been clinically linked to greater morbidity and, in the worst-case scenario, death through the rupture and bleeding of the tube. This emphasizes the importance of preventive measures in healthcare services, since prevention, prompt treatment, and early diagnosis of salpingitis can be effectively undertaken to reduce the incidence of ectopic pregnancies. Better epidemiological surveillance and molecular understanding of tubal failure can also contribute to the identification of women at highest risk, thus directing specific interventions [ 15 ].

Salpingitis or inflammation of the fallopian tubes is a noteworthy gynecological condition whose implications are far ranging and affect the reproductive health of women. It is also connected closely with pelvic inflammatory disease (PID) and is among the most common causes of tubal factor infertility and ectopic pregnancy. Besides its acute presentation, salpingitis is an etiological factor in reproductive long-term morbidity in geographic regions of late diagnosis or inadequate treatment [ 1 ]. The incidence of salpingitis is high in the world, and the prevalence and consequences differ significantly by geography. In underprivileged areas, poor screening and treatment enable infection to develop chronic forms that progressively destroy the structure of the tubes without symptoms. Even in highly developed healthcare environments, subclinical cases are not always noticeable until complications arise, which demonstrates the deficiency of the existing diagnostic methods and procedures [ 2 ]. Salpingitis is activated by complex immune and inflammatory responses in the fallopian tubes biologically. These events cause epithelial damage, ciliary dysfunction, and fibrotic remodeling, which compromise gametic and embryonic transportation [ 3 ]. Prolonged inflammatory conditions also change the microenvironment of the tubes, forming an environment that is predisposed to infertility and abnormal implantation. These mechanisms are important in attributing infection to reproductive dysfunction [ 4 ]. Recent breakthroughs in molecular biology and immunology have given more details about the pathogenesis of salpingitis. Cytokine signaling, pathogen-host interaction, and epigenetic changes are becoming more accepted to be the drivers of tube pathology. Moreover, omics technologies have enabled the identification of candidate biomarkers to be used as early detectives and prognosticators, which can be translated into clinical practice [ 4 , 5 ]. This review discusses the molecular pathology, biomarker discovery, and translational aspects of salpingitis in the pathophysiology of infertility and ectopic pregnancy. It will be combining epidemiological, mechanistic, and clinical data to give a holistic view of the impact of salpingitis on reproductive outcomes. These insights are critical toward the progress of specific interventions and enhancing the management of patients in reproductive medicine. A systematic literature review was performed in PubMed, Scopus, Web of Science, and Google Scholar (January 2000–December 2025) with various combinations of keywords based on salpingitis, tubal infertility, and ectopic pregnancy. As this review is not systematic but narrative, we have not used PRISMA screening and risk-of-bias assessment. Google Scholar was used solely to find more peer-reviewed sources, and the duplicates were eliminated manually. English-language articles that contained clinical, molecular, or epidemiologic information in regard to tubal pathology and reproductive outcomes were included. Salpingitis: fallopian inflammation, infectious or not. PID (pelvic inflammatory disease): this is a general infection of the upper genital tract, one of the elements is salpingitis. Hydrosalpinx: fallopian tube obstructed and inflamed chronically with fluid due to salpingitis. Chronic endometritis: focal inflammation of the endometrium; can be associated with salpingitis. Tubal factor infertility: associated with structural or functional tubal pathology. Salpingitis: fallopian inflammation, infectious or not. PID (pelvic inflammatory disease): this is a general infection of the upper genital tract, one of the elements is salpingitis. Hydrosalpinx: fallopian tube obstructed and inflamed chronically with fluid due to salpingitis. Chronic endometritis: focal inflammation of the endometrium; can be associated with salpingitis. Tubal factor infertility: associated with structural or functional tubal pathology.

Antibiotic treatment is the mainstay in the management of salpingitis, and regimens are generally directed against Chlamydia trachomatis , Neisseria gonorrhoeae , and anaerobic bacteria. Doxycycline or azithromycin is frequently used with cephalosporins to offer broad-spectrum coverage. Early antibiotic treatment may help to clear the infection as well as soothe the acute symptoms, but it has little or no effect in avoiding long-term sequelae such as infertility or ectopic pregnancy. Delayed diagnosis and less than full adherence are further detrimental to therapeutic outcomes, so timely intervention is very important [ 44 ]. Rising antimicrobial resistance is a significant obstacle in the management of salpingitis. Resistance to macrolides, tetracyclines, and fluoroquinolones has been reported with increasing frequency in N. gonorrhoeae , and with emerging resistance to these and other agents in Mycoplasma genitalium , treatment becomes more difficult. This trend is resulting in suboptimal efficacy of standard regimens and requires surveillance-guided therapy [ 45 ]. Figure  19 shows the major diagnostic barriers that delay translation into clinical care. Fig. 19 Barriers to accurate diagnosis and clinical translation in salpingitis Barriers to accurate diagnosis and clinical translation in salpingitis Assisted reproductive technologies (ART) offer essential solutions to infertile women with salpingitis and in case of irreversible damage to the tubes. Another procedure that circumvents damaged tubes is the case of in vitro fertilization (IVF), where oocytes are fertilized in the laboratory and transferred to the uterus. The success rates are good as a whole, but when conditions like hydrosalpinx are not treated, then the implantation and pregnancy results become low [ 46 ]. The latest developments with ART have also increased reproductive opportunities. Cases that include concomitant male factor infertility are managed using intracytoplasmic sperm injection (ICSI), as preimplantation genetic testing is used to improve embryo selection and implantation rate. The cumulative live birth rates are also raised by innovations in the cryopreservation and embryo culture systems that enable the flexibilities of embryo transferring [ 47 ]. Figure  20 shows the Integration of biomarker modalities for enhanced diagnostic accuracy in salpingitis. Fig. 20 Integration of biomarker modalities for enhanced diagnostic accuracy in salpingitis Integration of biomarker modalities for enhanced diagnostic accuracy in salpingitis