Infertility Due to Hydrosalpinx and Chronic Endometritis: Diagnosis and Management

PART 1: HYDROSALPINX

Pathophysiology and Impact on Fertility

• Mechanical reflux: Hydrosalpinx fluid can reflux into the uterine cavity, directly washing out embryos or altering the endometrial environment
• Toxic effect: The fluid contains cytokines, prostaglandins, and reactive oxygen species that are embryotoxic
• Endometrial receptivity: Hydrosalpinx fluid impairs expression of endometrial adhesion molecules (e.g., integrins, leukemia inhibitory factor) that are necessary for implantation
• Altered uterine contractility: The fluid may alter myometrial peristalsis

Etiology

• Pelvic inflammatory disease (PID), particularly Chlamydia trachomatis and Neisseria gonorrhoeae
• Endometriosis
• Prior pelvic or abdominal surgery
• Appendicitis with peritonitis

Diagnosis

• The primary screening tool
• Shows a fluid-filled, elongated, folded adnexal structure with characteristic "incomplete septa" (cogwheel sign on cross-section)
• Sensitivity ~95% for detecting hydrosalpinx

• Demonstrates the dilated tube and confirms distal occlusion
• Useful for evaluating bilateral disease and proximal patency simultaneously

• The gold standard for tubal assessment
• Provides direct visualization and allows chromopertubation
• Also permits concurrent surgical intervention

• Can sometimes show retrograde flow of saline into the tube

• Reserved for complex cases when ultrasound is inconclusive; provides excellent soft-tissue detail

Management

Surgical Options

• Salpingectomy and laparoscopic tubal occlusion (LTO) significantly increased clinical pregnancy rates vs. no treatment (OR 2.24 and 2.55 respectively)
• Salpingectomy and ultrasound-guided aspiration significantly increased ongoing pregnancy rates vs. no treatment
• LTO achieved the highest SUCRA ranking for live birth rate
• No intervention showed significant differences in live birth rate between active treatments, though all active treatments outperformed expectant management

• Clips or bipolar coagulation of the proximal tube prevents fluid from reaching the uterine cavity
• A reasonable alternative when salpingectomy is technically difficult (e.g., dense adhesions, poor ovarian reserve concerns)
• Preserves the possibility of future tubal surgery, though this is rarely relevant in IVF-bound patients
• The 2025 NMA ranked LTO as highly effective and potentially safer with regard to ovarian reserve impact than salpingectomy

• Can be performed under hysteroscopic guidance
• Useful when laparoscopy carries high surgical risk
• Less outcome data available compared to laparoscopic approaches

• Minimally invasive; done at time of egg retrieval or shortly before
• Significantly improves ongoing pregnancy rates vs. no treatment per 2025 NMA
• High recurrence rate (fluid re-accumulates) is the main drawback
• Reserved for patients who decline surgery or are poor surgical candidates

• Ultrasound-guided aspiration followed by instillation of a sclerosing agent (e.g., tetracycline, ethanol)
• The 2025 NMA found sclerotherapy significantly increased live birth rate vs. no treatment in observational data, and was ranked safer regarding ovarian stimulation response
• Limited RCT data; not yet first-line

• Creation of a new tubal opening - can be considered in younger patients (<35 years) with mild distal disease, intact tubal mucosa, and absent or minimal adhesions
• Pregnancy rates: 30-34.6% following salpingostomy in well-selected patients
• Associated with ~7.9% ectopic pregnancy rate
• Should be followed by IVF if pregnancy does not occur within 12-18 months
• Not recommended as a hydrosalpinx treatment when IVF is the primary plan

Decision Framework

Key point: Any active treatment is superior to expectant management before IVF. The choice between salpingectomy and LTO depends on surgical access, tube viability, and ovarian reserve concerns (as salpingectomy near the ovary could theoretically reduce ovarian reserve if the blood supply is compromised). - Berek & Novak's Gynecology, p. 2061

PART 2: CHRONIC ENDOMETRITIS (CE)

Definition and Prevalence

• ~2.8% in the general infertile population
• 7-14% in patients with recurrent pregnancy loss (RPL)
• Up to 56% in patients with documented recurrent pregnancy loss in some series
• 14-67% in patients with recurrent implantation failure (RIF) undergoing IVF

Etiology and Associated Conditions

1. Chronic pelvic inflammatory disease - most common
2. Retained gestational tissue - post-partum or post-abortion
3. Intrauterine contraceptive devices
4. Tuberculosis - from miliary spread or tuberculous salpingitis (important in endemic regions; always consider in recent emigrants)
5. STIs - Chlamydia trachomatis is particularly important; may be associated with both acute and chronic infiltrates; the organism may not be detected by culture
6. Non-specific (idiopathic) - ~15% of cases have no identifiable cause

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 928
• Robbins & Kumar Basic Pathology

Mechanisms Linking CE to Infertility

• Altered uterine receptivity: Inflammation dysregulates expression of adhesion molecules (integrins, L-selectin ligand, HOXA-10) and cytokines required for embryo implantation
• Endometrial microbiome disruption: Pathological bacteria (particularly Gardnerella, Streptococcus, Enterococcus, Escherichia coli) may outcompete the protective Lactobacillus-dominant microbiome
• Altered NK cell activity: Uterine natural killer (uNK) cells are critical for successful trophoblast invasion; CE alters their number and function
• Altered secretory transformation: The inflammatory milieu impairs normal secretory phase maturation of the endometrium, reducing the implantation window

Diagnosis

1. Endometrial Biopsy - Histopathology (Gold Standard)

• Performed in the mid-luteal phase (days 20-24 of the cycle)
• The hallmark finding is plasma cells in the endometrial stroma (Fig. 22.20D above)
• Standard H&E may miss plasma cells in the late secretory phase (when the stroma is decidualized and plasma cells are harder to distinguish)
• Immunohistochemistry for CD138 (syndecan-1) - the current gold standard technique; CD138 is a plasma cell surface marker that allows unambiguous identification even when H&E is equivocal
  • The diagnosis of CE requires CD138-staining for reliability - Creasy & Resnik's Maternal-Fetal Medicine

2. Hysteroscopy

• Provides direct visualization of the endometrial cavity
• Hysteroscopic findings suggestive of CE:
  • Stromal edema (the most common finding)
  • Micropolyps (small polypoid projections <1 mm, particularly at the endometrial surface near the tubal ostia)
  • Focal or diffuse hyperemia (strawberry pattern)
• The absence of endometrial hyperemia and edema on fluid hysteroscopy has a high negative predictive value of 98.8% - making normal hysteroscopy very useful for ruling out CE
• Hysteroscopy is less specific than CD138-stained biopsy but provides additional information about the cavity - Creasy & Resnik's MFM

3. Microbiological Culture / PCR

• Endometrial culture or endometrial fluid PCR can identify causative organisms
• However, culture is frequently negative even in histologically confirmed CE (organisms may not grow)
• 16S rRNA sequencing or next-generation sequencing of the endometrial microbiome is increasingly used in research settings and emerging clinical practice
• If infection is suspected clinically, antibiotic therapy is indicated even with negative cultures - Robbins & Kumar

Diagnostic Algorithm

Infertility workup (especially RIF or RPL)
    ↓
Hysteroscopy (screening: micropolyps, hyperemia, edema?)
    ↓
Endometrial biopsy with H&E + CD138 immunostaining
    ↓
Positive (plasma cells in stroma) → Confirm CE
    ↓
Endometrial culture / PCR for pathogens
    ↓
Treat empirically or targeted antibiotic therapy
    ↓
Repeat biopsy 4-6 weeks post-treatment to confirm resolution

Management

Antibiotic Therapy (First-Line)

• Doxycycline 100 mg twice daily × 14 days (most widely used; covers Chlamydia, Mycoplasma, and many gram-positives)

• Metronidazole 500 mg twice daily × 14 days (for anaerobes, Gardnerella)
• Ciprofloxacin 500 mg twice daily × 14 days (for gram-negative organisms)
• Some centers use a combination (doxycycline + metronidazole or amoxicillin-clavulanate)
• For tuberculous endometritis: standard ATT (4-drug regimen for 6 months) is required

• A repeat endometrial biopsy with CD138 staining 4-6 weeks after completing antibiotics is recommended before proceeding with embryo transfer
• Persistent CE after first-line antibiotics may require a second course with a different agent

Emerging / Adjunctive Therapies

• Clinical pregnancy rate of 50.5%, ongoing pregnancy rate 40.1%, and live birth rate 41.2% across antibiotic, probiotic, and nutraceutical interventions
• Probiotics (Lactobacillus-based preparations) may support restoration of a Lactobacillus-dominant endometrial microbiome after antibiotics
• The evidence base is limited with significant heterogeneity; standardized diagnostic criteria and larger RCTs are needed

Effect of Treatment on IVF Outcomes

• Higher implantation rates
• Higher clinical pregnancy rates
• Reduced miscarriage rates
• Most studies recommend deferring embryo transfer until resolution is confirmed histologically

SUMMARY TABLE

Recent Evidence Updates

• [Systematic Review 2025, PMID 38764191] (Pérez-Milán et al.): Salpingectomy and LTO both significantly improve clinical pregnancy rates before IVF. LTO may be the preferred option for live birth rate by SUCRA ranking. Sclerotherapy appears safe regarding ovarian reserve. No treatment significantly surpasses others for live birth rate - treatment choice can be individualized.
• [Systematic Review 2026, PMID 41684313] (Doroftei et al.): Microbiota-targeted therapies (antibiotics, probiotics, nutraceuticals) show promising pregnancy outcomes in CE-associated RIF (LBR ~41%), but evidence quality is low and standardized protocols are lacking.
• [Systematic Review/Meta-Analysis 2025, PMID 39821822]: A meta-analysis explored the overlap between CE and endometriosis, suggesting shared inflammatory pathways - clinicians should screen for CE in patients with endometriosis-associated infertility.