An exploratory study on the impact of endocrine and infectious comorbidities on reproductive outcomes after Palmer-type neosalpingostomy

Abstract

Background: Hydrosalpinx remains a major cause of female infertility, with Palmer-type neosalpingostomy representing a fertility-preserving alternative to salpingectomy in selected patients. While disease severity is a well-established prognostic factor, the contribution of endocrine and infectious comorbidities to reproductive outcomes after tubal reconstruction remains poorly characterized. Patients, Materials and Methods: This retrospective cohort study included 160 women with hydrosalpinx who underwent Palmer-type neosalpingostomy between January 2018 and December 2024 at Independenţa VitaPlus Hospital, Craiova, Romania. Endocrine and infectious comorbidities were systematically assessed preoperatively, including polycystic ovary syndrome (PCOS), thyroid dysfunction, obesity, diabetes, pelvic inflammatory disease (PID), and urinary tract infections (UTI). Pregnancy outcomes were evaluated over a 24-month follow-up period. Statistical analysis included Kaplan–Meier survival estimates and multivariate logistic regression to identify independent predictors of clinical pregnancy. Results: PCOS (30.6%), PID (28.2%), and UTI (18.1%) were the most common comorbidities. Hydrosalpinx severity was the only independent predictor of clinical pregnancy [odds ratio (OR) 0.38, p<0.001]. Although endocrine and infectious comorbidities did not reach statistical significance in multivariate models, Kaplan–Meier analysis revealed observable prolongation in time-to-pregnancy for patients with PID, PCOS, or obesity. Increasing infectious burden (≥2 pathogens) was associated with higher pelvic adhesion rates and reduced conception probabilities. Conclusions: Hydrosalpinx severity remains the main determinant of reproductive prognosis after Palmer-type neosalpingostomy. However, endocrine and infectious comorbidities exert clinically relevant negative effects, supporting a comorbidity-informed approach to patient selection and preoperative optimization. Prospective, multicenter studies with in vitro fertilization (IVF) comparison arms are warranted to refine prognostic models and optimize fertility counseling and treatment strategies.

Introduction

Infertility affects approximately 15% of couples worldwide and represents a growing public health issue with significant medical, psychological, and socioeconomic consequences [1, 2]. Tubal factor infertility accounts for up to 30% of female infertility cases, with hydrosalpinx being one of the most frequently identified lesions [3]. This condition has a well-documented detrimental impact on fertility, both in natural conception and assisted reproduction, as hydrosalpingeal fluid reduces implantation and pregnancy rates in in vitro fertilization (IVF) through embryotoxicity, local inflammation, and mechanical wash-out of the embryo [4, 5].

Surgical treatment remains central to hydrosalpinx management. While salpingectomy is the standard of care prior to IVF, Palmer-type neosalpingostomy provides a fertility-preserving alternative for women wishing to conceive naturally by restoring tubal patency and anatomical continuity [6, 7]. However, postoperative outcomes depend not only on the severity of tubal disease but also on systemic and infectious comorbidities. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in reproductive age women, causes anovulatory infertility through hyperandrogenism, insulin resistance, elevated anti-Müllerian hormone (AMH) and impaired endometrial receptivity [8, 9]. Thyroid dysfunction, both overt and subclinical, further contributes to ovulatory disorders, implantation failure, and miscarriage risk [10, 11, 12], while obesity and diabetes negatively influence fertility via endocrine disruption, chronic inflammation, and oxidative stress [13, 14].

Genital tract infections – particularly Chlamydia trachomatis, Mycoplasma, Ureaplasma, and bacterial vaginosis – represent critical determinants of tubal damage, chronic pelvic inflammatory disease (PID), and recurrent hydrosalpinx [14, 15, 16]. Additional factors such as uterine fibroids, which can distort the uterine cavity and induce local inflammation [17], and metabolic comorbidities may further impair ovulation and implantation [8, 14]. Despite advances in reproductive surgery, few studies have evaluated the combined influence of endocrine and infectious comorbidities on fertility outcomes following Palmer-type neosalpingostomy, as most research has focused mainly on anatomical or technical aspects [15, 17, 18]. Therefore, this study aimed to assess the prevalence and impact of these comorbidities on reproductive prognosis in women with hydrosalpinx undergoing Palmer-type neosalpingostomy.

Aim

This study aimed to assess the independent and cumulative effects of endocrine and infectious comorbidities on reproductive outcomes following Palmer-type neosalpingostomy in women with hydrosalpinx and to determine how these systemic factors interact with the anatomical severity of disease. The ultimate goal was to support a more individualized, comorbidity-informed approach to patient selection and preoperative optimization in fertility-preserving surgical management.

Patients, Materials and Methods

Study population

This was a retrospective cohort study conducted at Independenţa VitaPlus Hospital, Craiova, Romania, including women diagnosed with hydrosalpinx who underwent Palmer-type neosalpingostomy between January 2018 and December 2024. Eligible patients were preoperatively evaluated through clinical examination, transvaginal ultrasound (US), hysterosalpingography, and/or laparoscopy to confirm the diagnosis and assess tubal disease severity. Comorbidities were identified through clinical history, biochemical tests, and microbiological investigations.

Endocrine disorders included PCOS, thyroid dysfunction, obesity, and diabetes mellitus. Infectious conditions included PID and urinary tract infections (UTI). Additional gynecological conditions such as endometriosis and uterine fibroids were also recorded.

Surgical procedure and postoperative management

Hydrosalpinx severity was classified intraoperatively as minor, moderate, or severe based on the extent of tubal distension, wall thickening, fimbrial agglutination, and the presence of peritubal adhesions. Tubal reconstructive surgery was performed using the Palmer-type neosalpingostomy technique with atraumatic opening of the distal tube and eversion of fimbriae.

All patients underwent preoperative genital tract screening as part of the standard infertility workup. Vaginal and endocervical swabs were obtained prior to surgery and analyzed using culture and/or polymerase chain reaction (PCR) techniques for common genital pathogens. Testing included Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Escherichia coli, and other urogenital bacteria. Patients with positive results received targeted antibiotic therapy according to microbiological findings before surgical intervention.

Patients were followed postoperatively with regular gynecological and US evaluations to monitor tubal patency, detect potential complications, and assess fertility outcomes.

Outcomes

All patients were followed for up to 24 months postoperatively to assess spontaneous conception. The primary outcome was the clinical pregnancy rate, defined as the presence of a gestational sac with fetal heartbeat on transvaginal US. Secondary outcomes included time to conception and the association between comorbidities and reproductive prognosis.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics. Continuous variables were tested for normality using the Shapiro–Wilk test and expressed as mean ± standard deviation (SD) or median (interquartile range, IQR), as appropriate. Associations between comorbidities and pregnancy rates were evaluated using χ2 (chi-squared) tests, odds ratios (ORs), and Kaplan–Meier survival analysis with log-rank tests.

Variables with p<0.10 in univariate analyses were included in the multivariate logistic regression using a stepwise forward conditional method to identify independent predictors of clinical pregnancy. Missing data were handled through pairwise deletion (available-case analysis).

Given the small sample size and the exploratory nature of this study, variables with fewer than 10 cases were excluded from multivariate analyses to avoid model instability. Rare conditions (e.g., arrhythmia, nodular goiter) were grouped under broader categories (“other endocrine disorders”, “other comorbidities”). The statistical power for subgroup analyses was limited; therefore, results should be interpreted as exploratory.

A post-hoc power analysis using G*Power version 3.1 indicated that the study had approximately 72% power to detect moderate effect sizes (OR 1.8–2.0) at α=0.05.

A p-value <0.05 was considered statistically significant. All analyses were performed using Statistical Package for the Social Sciences (SPSS) v.26.0 (IBM, Armonk, NY, USA).

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Independenţa VitaPlus Hospital (Protocol Code No. 1/2025, date of approval 2025-01-15). Informed consent was obtained from all participants prior to surgery.

Results

PCOS, PID, and UTI were the most frequent comorbidities, followed by uterine fibroids, obesity, and hypothyroidism (Table 1). The comorbidity network (Figure 1) illustrates frequent overlaps, particularly between PCOS and metabolic or infectious disorders.

Table 1.

Baseline prevalence of comorbidities in the study cohort (n=160)

Comorbidity	Prevalence [%]
PCOS	30.6
PID	28.2
UTI	18.1
Uterine fibroids	16.7
Obesity	14.4
Hypothyroidism	12.5
Endometriosis	5.0
Type 2 diabetes	3.1
Hypertension	1.3
Arrhythmia	4.6
Nodular goiter	1.3

PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection. Rare endocrine disorders (arrhythmia, nodular goiter, etc.) were grouped under “Other endocrine disorders” for regression analyses

Figure 1.

Comorbidity network of the study cohort (n=160). Node size reflects the relative frequency of each condition, while edge thickness indicates the strength of co-occurrence between comorbidities. PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

Histopathological assessment

In all examined cases, the main histopathological findings consisted of marked dilatation of the fallopian tube lumen and structural alterations of the salpinx wall, particularly involving the mucosa and muscular layers. Compared to normal plicated architecture, the mucosal folds were markedly reduced or flattened, with only limited areas preserving residual normal morphology. The epithelial lining appeared predominantly attenuated due to luminal distension and frequently showed atrophy with ciliary loss, without evidence of atypia or dysplasia. The muscular layer exhibited a disorganized pattern, characterized by alternating thinned regions and areas of fibrosis or hyalinization. Vascular changes were variably expressed, ranging from hyperemic and thick-walled vessels to cases with reduced vascular density and preserved morphology. Inflammatory infiltrates were generally mild and focal, composed mainly of lymphocytes and plasma cells with a predominantly perivascular distribution (Figure 2A, 2B; Figure 3A, 3B).

Figure 2.

(A and B) Histological section of the Fallopian tube showing hydrosalpinx. The tubal lumen is markedly dilated and lined by flattened epithelium with loss of cilia, a residual normal fold and the muscular wall is thinned. Hematoxylin–Eosin (HE) staining: (A) ×40; (B) ×100

Figure 3.

(A and B) Histological section of the Fallopian tube showing hydrosalpinx. Distended tubal lumen lined by flattened epithelium with loss of mucosal folds, thin muscular layer, and several dilated, hyperemic vessels. HE staining: (A) ×40; (B) ×100

Microbiological findings

Genital tract infections were identified in 48 (30%) patients prior to surgery. The most frequently isolated pathogens were Chlamydia trachomatis (37.5%), Ureaplasma urealyticum (29.2%), Mycoplasma hominis (18.8%), and Escherichia coli (14.5%). Mixed infections, defined as the presence of ≥2 pathogens, were detected in 10.4% of cases, most commonly combinations of Chlamydia trachomatis with Ureaplasma urealyticum or Mycoplasma hominis. All patients with positive microbiological results received targeted antibiotic therapy prior to surgical intervention.

Special attention should be given to patients with a history of tuberculosis infection, as oxidative stress disorders and mitochondrial dysfunction may severely disrupt coagulation.

Statistical analysis

Women with PCOS were significantly older and had lower AMH levels compared with those without (both p<0.001). Uterine fibroids were associated with slightly lower AMH (p=0.037), while no significant differences in age or AMH were observed for PID, UTI, or obesity (Table 2).

Table 2.

Age and AMH levels (mean ± SD) in women with and without comorbidities

Comorbidity	Age with [years]	Age without [years]	p -value	AMH with [ng/mL]	AMH without [ng/mL]	p -value
PCOS	37.0±3.3	33.9±4.9	<0.001	1.45±0.63	2.64±0.88	<0.001
PID	34.4±5.3	35.7±3.9	0.101	2.33±1.01	2.03±0.95	0.066
UTI	34.3±5.0	35.5±4.3	0.176	2.25±1.08	2.12±0.95	0.505
Uterine fibroid	35.1±4.0	35.2±4.7	0.873	2.44±0.93	2.06±0.98	0.037
Obesity	34.8±5.1	35.3±4.4	0.672	2.19±0.94	2.14±0.99	0.790

AMH: Anti-Müllerian hormone; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; SD: Standard deviation; UTI: Urinary tract infection

Pregnancy rates did not differ significantly by comorbidity status. Slightly higher rates were observed in women with obesity (46.7%) and uterine fibroids (38.9%), while lower rates occurred in those with PID (27.9%), UTI (23.1%), or hypothyroidism (22.2%) (Table 3).

Table 3.

Pregnancy outcomes according to comorbidity status

Comorbidity	n with comorbidity	Pregnancies with comorbidity	Pregnancy rate [%]	n without comorbidity	Pregnancies without comorbidity	Pregnancy rate [%]
PCOS	66	21	31.8	108	33	30.6
PID	61	17	27.9	113	37	32.7
UTI	39	9	23.1	135	45	33.3
Uterine fibroids	36	14	38.9	138	40	29.0
Obesity	30	14	46.7	144	40	27.8
Hypothyroidism	27	6	22.2	147	48	32.7
Endometriosis	8	3	37.5	166	51	30.7
Type 2 diabetes	5	1	20.0	169	53	31.4
Hypertension	2	0	0.0	172	54	31.4
Arrhythmia	10	1	10.0	164	53	32.3
Nodular goiter	2	0	0.0	172	54	31.4

n: No. of patients; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

In unadjusted analyses (Table 4), none of the comorbidities reached statistical significance for clinical pregnancy. Obesity showed a non-significant trend toward increased odds [OR 1.97, 95% confidence interval (CI) 0.88–4.42], while PID, UTI, and PCOS tended to reduce the odds. Rare conditions such as hypertension, arrhythmia, and nodular goiter could not be reliably evaluated due to very low numbers.

Table 4.

Unadjusted ORs for clinical pregnancy by comorbidity

Comorbidity	OR (unadjusted)	95% CI lower	95% CI upper	Pregnancy+ & Comorbidity+	Pregnancy– & Comorbidity+	Pregnancy+ & Comorbidity–	Pregnancy– & Comorbidity–
PID	0.65	0.32	1.29	17	44	37	62
UTI	0.51	0.22	1.16	9	30	45	76
PCOS	0.86	0.44	1.68	21	45	33	61
Uterine fibroids	1.34	0.62	2.88	14	22	40	84
Obesity	1.97	0.88	4.42	14	16	40	90
Hypothyroidism	0.60	0.23	1.59	6	21	48	85
Endometriosis	1.33	0.31	5.74	3	5	51	101
Type 2 diabetes	0.55	0.06	5.02	1	4	53	102
Hypertension	0.34	0.02	7.48	0	2	54	104
Arrhythmia	0.25	0.03	1.96	1	9	53	97
Nodular goiter	0.34	0.02	7.48	0	2	54	104

CI: Confidence interval; OR: Odds ratio; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection. Due to small numbers (<10 cases), rare conditions such as arrhythmia and nodular goiter were not included in multivariate analysis

Time-to-pregnancy analysis stratified by combined PID/PCOS status showed significant differences among the four subgroups (log-rank χ2=50.7, p<0.001). Patients with concomitant PID and PCOS (PID+/PCOS+) exhibited the lowest probability of conception, while those without either condition (PID−/PCOS−) had the most favorable outcomes (Figure 4).

Figure 4.

Kaplan–Meier curves for time to clinical pregnancy by combined PID/PCOS status. Women with PID+/PCOS+ had the lowest conception rates, while PID−/PCOS− had the best outcomes (log-rank χ2=50.7, p<0.001). PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease

The distribution of comorbidities by hydrosalpinx severity is shown in Table 5. While the prevalence of PCOS was relatively balanced across severity grades (~40–46%), obesity was more frequent in minor forms (28.9%) and declined in severe cases (12.5%). Conversely, PID prevalence increased with disease severity, from 22.2% in minor cases to 46.6% in severe hydrosalpinx.

Table 5.

Distribution of comorbidities according to hydrosalpinx severity

Hydrosalpinx severity	n	PCOS prevalence [%]	Obesity prevalence [%]	PID prevalence [%]
Minor	45	44.4	28.9	22.2
Moderate	24	45.8	20.8	41.7
Severe	88	37.5	12.5	46.6

n: No. of patients; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease

Figure 5.

Unadjusted ORs for clinical pregnancy by comorbidity. OR: Odds ratio; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

The prevalence of pelvic adhesions increased with hydrosalpinx severity (Table 6), reaching over 80% in severe cases. Among moderate and severe hydrosalpinx, women with PCOS, obesity, or PID showed particularly high adhesion rates (>70%).

Table 6.

Prevalence of pelvic adhesions according to hydrosalpinx severity and selected comorbidities

Hydrosalpinx severity	Comorbidity	n with comorbidity	n with adhesions	Adhesions prevalence [%]
Minor	PCOS	20	5	25.0
Minor	Obesity	13	2	15.4
Minor	PID	10	2	20.0
Moderate	PCOS	11	7	63.6
Moderate	Obesity	5	4	80.0
Moderate	PID	10	7	70.0
Severe	PCOS	33	26	78.8
Severe	Obesity	11	9	81.8
Severe	PID	41	34	82.9

n: No. of patients; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease

Pelvic adhesions were frequent among women with comorbidities, being most prevalent in endometriosis (75.0%), followed by UTI (61.5%) and PID (60.7%) (Table 7).

Table 7.

Prevalence of pelvic adhesions according to selected comorbidities

Comorbidity	n with comorbidity	n with adhesions	Adhesions prevalence [%]
PID	61	37	60.7
Endometriosis	8	6	75.0
UTI	39	24	61.5

n: No. of patients; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

Kaplan–Meier analysis showed no significant difference in time to clinical pregnancy between women with one comorbidity and those with ≥2 comorbidities (log-rank p=0.99) (Figure 6).

Figure 6.

Kaplan–Meier curves by cumulative comorbidity burden

Among the 160 women included, all had at least one comorbidity. The pregnancy rate was 38.3% in those with a single comorbidity and decreased to 31.0% in those with ≥2 comorbidities (Table 8). The cumulative burden of comorbidities was associated with a downward trend in pregnancy rates, supporting the hypothesis that multifactorial impairment has a greater impact than any single factor.

Table 8.

Pregnancy outcomes by cumulative comorbidity burden

Comorbidity burden	n	Pregnancies	Pregnancy rate [%]
1	60	23	38.3
≥2	100	31	31.0

n: No. of patients

Multivariate logistic regression confirmed hydrosalpinx severity as an independent negative predictor of clinical pregnancy (OR 0.38, p<0.001). Variables with fewer than 10 cases (e.g., arrhythmia, nodular goiter) were excluded from the regression model to avoid instability. Age and AMH were not significant, while the comorbidity score showed a nonsignificant negative trend (OR 0.67, p=0.156) (Table 9; Figure 7).

Table 9.

Multivariate logistic regression for clinical pregnancy

Variable	OR	95% CI lower	95% CI upper	p -value
Age	1.02	0.92	1.13	0.734
AMH	0.97	0.59	1.58	0.897
Severity grade*	0.38	0.25	0.57	<0.001
Comorbidity score †	0.67	0.38	1.17	0.156

*Coded as minor: 0, moderate: 1, severe: 2; †Coded as 0, 1, or ≥2 comorbidities; AMH: Anti-Müllerian hormone; CI: Confidence interval; OR: Odds ratio. Rare variables (<10 cases), such as arrhythmia and nodular goiter, were excluded from the regression model to ensure statistical stability

Figure 7.

Adjusted ORs for clinical pregnancy according to age, AMH, hydrosalpinx severity, and comorbidity burden. AMH: Anti-Müllerian hormone; OR: Odds ratio

The presence of genital tract infections was not associated with significant differences in pelvic adhesions or clinical pregnancy rates compared with negative cultures (Table 10).

Table 10.

Association of genital tract infections with pelvic adhesions and clinical pregnancy

Infection status	n	Pelvic adhesions n (%)	Clinical pregnancy n (%)
Any infection	48	28 (58.3%)	16 (33.3%)
Negative culture	112	67 (59.8%)	38 (33.9%)

n: No. of patients

Increasing infection burden was associated with higher adhesion rates and a marked reduction in clinical pregnancy, most pronounced in women with ≥2 infections (11.8%) (Table 11).

Table 11.

Association of multiple genital tract infections (PID/UTI) with pelvic adhesions and clinical pregnancy (n=160)

Infection burden	n	Pelvic adhesions n (%)	Clinical pregnancy n (%)
0 infections	77	46 (59.7%)	30 (39.0%)
1 infection	66	37 (56.1%)	22 (33.3%)
≥2 infections	17	12 (70.6%)	2 (11.8%)

n: No. of patients; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

Kaplan–Meier analysis demonstrated a stepwise decrease in time-to-pregnancy according to infection burden (Figure 8). The log-rank test confirmed highly significant differences among the three groups (χ2=20 633.5, p<0.001).

Figure 8.

Kaplan–Meier curves for time to pregnancy stratified by obesity, PCOS, and PID. PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

Kaplan–Meier curves showed significantly lower pregnancy rates in women with obesity, PCOS, or PID compared with controls (all log-rank p<0.001). At 12 months, pregnancy rates were 40.0% in obese, 22.7% in PCOS, and 13.1% in PID patients (Figure 9A, 9B, 9C).

Figure 9.

Adjusted analysis identified hydrosalpinx severity as the only significant predictor of clinical pregnancy (OR 39.7 for minor vs. severe, p<0.001). Age, AMH, pelvic adhesions, and comorbidities were not significantly associated with outcomes (Table 12).

Table 12.

Adjusted ORs for clinical pregnancy after Palmer-type neosalpingostomy (n=160)

Predictor	Adjusted OR	95% CI	p -value
Age [per year]	1.05	0.92–1.20	0.449
AMH [ng/mL]	0.98	0.48–2.00	0.956
Severity: minor vs. severe	39.74	10.53–149.94	<0.001
Severity: moderate vs. severe	3.28	0.98–10.96	0.054
Pelvic adhesions (yes vs. no)	0.79	0.27–2.29	0.660
PCOS	0.59	0.17–2.11	0.420
PID	0.56	0.18–1.72	0.309
UTI	0.48	0.14–1.69	0.254
Uterine fibroid	2.11	0.61–7.34	0.240
Obesity	0.54	0.16–1.81	0.319
Hypothyroidism	1.36	0.36–5.17	0.648
Arrhythmia	0.32	0.05–1.94	0.217
Endometriosis	0.54	0.05–5.90	0.613

No. of observations (n): 160, events (clinical pregnancy/live birth): 49, non-events: 111; AMH: Anti-Müllerian hormone; CI: Confidence interval; OR: Odds ratio; PCOS: Polycystic ovary syndrome; PID: Pelvic inflammatory disease; UTI: Urinary tract infection

Discussions

In this retrospective study of 160 patients, we identified a high prevalence of endocrine and infectious comorbidities among women with hydrosalpinx, with a variable impact on reproductive parameters. Among these factors, the severity of tubal disease was the strongest predictor of outcomes, while endocrine and infectious comorbidities exerted subtle but consistent negative effects.

The comorbidity network highlights frequent interactions between endocrine and infectious conditions, particularly PCOS, obesity, and PID, which may amplify their cumulative impact on reproductive outcomes. Such multidimensional profiling could improve individualized risk stratification and treatment planning.

Comparison with literature

Our results align with previous evidence highlighting the multifactorial nature of fertility impairment in women with hydrosalpinx. The severity of tubal disease remains the main determinant of reproductive prognosis. Multiple studies have demonstrated significantly higher pregnancy rates in mild or moderate hydrosalpinx compared to severe disease [19].

In our cohort, infectious comorbidities (PID, UTI) were associated with lower pregnancy rates. This finding mirrors well-established data linking genital tract infections with tubal factor infertility. Chlamydia trachomatis, Ureaplasma, and Mycoplasma are known to induce chronic inflammation, fibrosis, and fimbrial dysfunction, which compromise tubal transport and endometrial receptivity [20, 21]. These mechanisms likely explain the lower reproductive success in this subgroup despite tubal reconstruction. Our microbiological findings are consistent with this pathogenic model. Chlamydia trachomatis was the most frequently isolated pathogen, followed by Ureaplasma urealyticum and Mycoplasma hominis. Mixed infections were present in more than 10% of cases, supporting the concept of an additive or synergistic effect of multiple pathogens on tubal injury and postoperative fertility. These results align with previous studies demonstrating that coinfections are associated with more severe tubal damage and lower conception rates [16, 22, 23]. Preoperative targeted antibiotic therapy may therefore be a critical component of optimizing reproductive outcomes after neosalpingostomy.

These findings reinforce the importance of systematic preoperative screening and targeted treatment of genital tract infections as an integral part of fertility-preserving surgical strategies.

Endometriosis emerged as another relevant comorbidity. Prior literature demonstrates that endometriosis negatively affects fertility through inflammatory, immunologic, and mechanical pathways, including altered folliculogenesis, disturbed pelvic anatomy, and impaired implantation [23, 24]. Our data showed lower pregnancy rates in women with concurrent endometriosis and hydrosalpinx, which is consistent with these mechanisms. Endometriotic adhesions may also worsen tubal damage, further limiting the benefit of neosalpingostomy.

A special issue concerns endometrioid adenofibroma of the ovary, which can reduce the likelihood of a normal pregnancy, with the chances decreasing significantly in the context of microbiome imbalance [25, 26].

An increase in oxidative stress markers (superoxide dismutase) represents a valuable indicator, signaling a high risk of unfavorable progression [27].

Uterine fibroids are a well-recognized but heterogeneous factor in fertility outcomes. Their impact depends on fibroid type, number, and location. Submucosal or cavity-distorting fibroids have consistently been associated with reduced pregnancy rates and improved outcomes after myomectomy [28]. Although our results showed only a nonsignificant negative trend, this may reflect the predominance of non-cavity-distorting fibroids in our cohort.

Endocrine factors, particularly PCOS and thyroid dysfunction, were frequent in our population. This mirrors their high prevalence in infertile populations. PCOS contributes to infertility through hyperandrogenism, anovulation, insulin resistance, and altered endometrial receptivity [29, 30]. Thyroid dysfunction, especially subclinical hypothyroidism, has been linked to reduced conception and increased miscarriage rates [31]. The subtle negative impact observed in our study is compatible with these pathophysiological pathways, though statistical significance may be limited by sample size.

Metabolic disorders such as obesity and diabetes also influence fertility through hormonal imbalance, chronic inflammation, and oxidative stress [16, 32]. Although not statistically significant in our cohort, these factors are biologically plausible contributors to reduced fecundity and may interact with tubal disease severity.

Additionally, environmental and occupational exposures, although not evaluated here, have been associated with adverse reproductive outcomes [33], suggesting that future studies should integrate these variables into prognostic models.

Taken together, our findings reinforce a multifactorial model of fertility impairment in women with hydrosalpinx:

▪ Tubal disease severity remains the primary determinant of reproductive outcomes.

▪ Infectious, endocrine, metabolic, and structural comorbidities exert additive or synergistic negative effects.

▪ Their presence may modulate the benefit expected from conservative tubal surgery.

These data support the need for comprehensive preoperative evaluation and personalized management strategies, including targeted treatment of infections, hormonal optimization, and correction of uterine pathology before or in parallel with neosalpingostomy. Future prospective studies with larger samples are needed to refine prognostic models and optimize patient selection.

Possible mechanisms

Several pathophysiological mechanisms may explain the associations between comorbidities and reproductive outcomes following Palmer-type neosalpingostomy for hydrosalpinx.

Polycystic ovary syndrome

PCOS is characterized by insulin resistance, hyperinsulinemia, and hyperandrogenism, leading to anovulation, impaired folliculogenesis, and reduced oocyte quality. These endocrine alterations, together with decreased endometrial receptivity, contribute to lower implantation rates and fertility potential [25, 26].

Pelvic inflammatory disease and urinary tract infections

Recurrent pelvic infections cause chronic inflammation, fibrosis, and peritubal adhesions, resulting in fimbrial dysfunction and impaired gamete transport. Inflammatory changes also affect the endometrial environment, further reducing implantation rates [20, 34].

Thyroid dysfunction

Subtle thyroid hormone alterations can disrupt the hypothalamic–pituitary–ovarian axis, impair ovulation and luteal function, and reduce endometrial receptivity, ultimately decreasing implantation and increasing early pregnancy loss [31, 35].

Obesity and metabolic disorders

Obesity is associated with systemic inflammation, insulin resistance, and altered steroidogenesis, which negatively influence ovulation and endometrial receptivity [33, 37]. The lower average age in this subgroup may have attenuated the detectable impact, acting as a confounding factor.

Environmental and occupational factors

Exposure to reproductive toxins such as sterilizing agents or antineoplastic drugs has been linked to adverse pregnancy outcomes and may exacerbate underlying reproductive vulnerabilities [33].

Impact of hydrosalpinx severity

In this study, the severity of tubal disease emerged as the strongest independent predictor of reproductive outcomes after Palmer-type neosalpingostomy. Patients with severe hydrosalpinx had a significantly lower likelihood of achieving a clinical pregnancy compared to those with mild or moderate disease, with an OR approaching 40-fold reduction in success rates. This finding emphasizes the prognostic weight of anatomical severity in determining postoperative fertility.

These results are fully consistent with previous studies demonstrating the negative impact of advanced hydrosalpinx on both spontaneous conception and assisted reproduction outcomes. Bayrak et al. reported a recurrence rate of 70% and a total pregnancy rate of only 7.5% after cuff neosalpingostomy in a poor-prognosis population, highlighting the limited effectiveness of conservative surgery in severe disease [15]. Similar findings have been echoed in other surgical series, where mild-to-moderate disease was associated with higher cumulative pregnancy rates [19].

The underlying mechanisms are likely multifactorial: advanced disease is associated with extensive tubal fibrosis, destruction of fimbrial architecture, and loss of ciliary function, leading to impaired oocyte pick-up and transport. In addition, chronic inflammation and adhesions further compromise tubal function and increase the risk of recurrence [38].

Taken together, these findings support the central role of hydrosalpinx severity in patient selection and counseling. In clinical decision-making, incorporating endometrioid adenofibroma and serous papillary adenofibroma cyst (SPAC) into the diagnostic algorithm for adnexal masses may help avoid overtreatment and guide more conservative, fertility-preserving approaches in appropriately selected patients [39, 40]. In cases of severe disease, conservative surgical options may have limited benefits, and alternative strategies such as salpingectomy followed by IVF should be considered to optimize reproductive outcomes.

Interpretation of non-significant results

Although several comorbidities showed trends toward lower pregnancy rates after Palmer-type neosalpingostomy, none reached statistical significance in multivariate analysis. This lack of significance likely reflects methodological and sample-related factors rather than the absence of a biological effect. Nevertheless, Kaplan–Meier curves revealed clinically relevant delays in time-to-pregnancy in patients with PID, PCOS, and obesity, suggesting a time-dependent reduction in fertility potential.

First, the sample size may have been insufficient to detect moderate effects, particularly for subgroups with lower prevalence such as PCOS and obesity. Statistical power is a critical determinant of significance, and small effect sizes often require larger cohorts for robust detection.

Second, heterogeneity in disease distribution and interaction effects may have diluted individual contributions. For example, PCOS often coexists with obesity and metabolic disorders, and PID may overlap with other infectious or inflammatory conditions, making it difficult to isolate their independent impact.

Third, age distribution and confounding factors may have attenuated observed associations. For instance, obese patients in our cohort were on average younger, potentially counterbalancing the expected negative reproductive impact.

These observations are consistent with previous reports showing that endocrine and infectious comorbidities may exert subtle but clinically meaningful effects that are not always statistically significant in smaller studies [11, 41]. PCOS, for example, is well known to affect ovulatory function and implantation, while PID and chronic infections impair tubal transport and endometrial receptivity [22, 42].

Therefore, the absence of statistical significance should not be interpreted as the absence of effect, but rather as a limitation in statistical power and study design. The observed negative trends for PID, UTI, and endocrine disorders underscore the need for larger, prospective studies to better quantify their impact on reproductive outcomes after conservative tubal surgery.

In addition to the individual impact of endocrine and infectious comorbidities, our findings suggest that their cumulative burden may play an important role in modulating postoperative reproductive outcomes. The downward trend in pregnancy rates observed in women with multiple comorbidities supports the hypothesis that multifactorial impairment exerts a greater negative effect than any single factor alone. This aligns with the concept of synergistic pathophysiological mechanisms – such as chronic inflammation, endocrine–immune interactions, and pelvic adhesions – that collectively reduce fertility potential. Future prospective studies should further explore how cumulative comorbidities influence prognosis and guide personalized treatment strategies.

We note that this type of female-specific surgical pathology significantly increases the risk of developing a major psychiatric comorbidity, namely depressive disorder associated with suicidal ideation [43, 44]. The risk of self-harming behavior is amplified in the presence of PCOS, metabolic syndrome, and thyroid dysfunction. In this context, psychiatric monitoring of the evolution of cases by a multidisciplinary team is required. The therapeutic approach to antidepressant medication requires significant personalization, namely avoiding medication with anticholinergic action (tricyclic antidepressants, Sertraline, non-psychotropic anticholinergic medication) [45] because cholinergic blockade promotes the stimulation of inflammatory processes and an increase in biological markers [interleukin-6 (IL-6) and tumor necrosis factor-alpha2 (TNF-α2)], thereby reducing neuroprotection and neurogenesis. Good therapeutic results for comorbid depression can be achieved by using an antidepressant without anticholinergic action (Trazodone) in combination with a latest-generation anti-inflammatory drug with antidepressant action (Celecoxib) [46]. In the current post-pandemic circumstances, patients who have undergone severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may present a significant evolutionary risk due to the potential for rapid activation of atypical inflammatory mechanisms and coagulation disorders. These risks persist during pregnancy, both peripartum and postpartum, requiring strict monitoring and a differentiated therapeutic approach [47].

Strengths, limitations, clinical implications, and future perspectives

This study has several notable strengths. It is among the few to assess the combined impact of endocrine and infectious comorbidities on reproductive outcomes after Palmer-type neosalpingostomy, using real-world data from a well-defined cohort. The detailed characterization of comorbidities, together with comorbidity network analysis, enabled a multifactorial understanding of how endocrine, infectious, and metabolic conditions may influence fertility outcomes. Kaplan–Meier analysis also revealed observable prolongation in time-to-pregnancy in patients with PID, PCOS, and obesity, despite the lack of statistical significance in multivariate models.

Several limitations should be acknowledged. The retrospective, single-center design may limit external validity and introduce potential selection and information biases. The relatively small sample size for less prevalent comorbidities, such as thyroid disorders and PCOS, may have limited statistical power. The absence of a comparative control group (e.g., IVF-treated patients) restricts direct benchmarking of fertility outcomes. Moreover, environmental, lifestyle, and occupational exposures were not assessed, potentially underestimating their contribution to reproductive prognosis. Potential selection and information biases are inherent to retrospective designs, and differences in follow-up duration may have influenced the estimation of cumulative pregnancy rates. External validation in independent cohorts is warranted to confirm the generalizability of these findings.

Despite these limitations, the study carries important clinical implications. Hydrosalpinx severity remains the strongest independent predictor of postoperative fertility, but the results highlight the additive or synergistic negative impact of endocrine and infectious comorbidities. This supports a multidimensional, comorbidity-informed approach to patient selection and preoperative optimization. Patients with mild or moderate disease may benefit from tubal reconstructive surgery after endocrine and infectious optimization, whereas those with advanced disease may achieve better outcomes with salpingectomy followed by IVF.

Importantly, although the efficacy of neosalpingostomy has been extensively evaluated, few studies have explored the cumulative impact of comorbidities on natural conception rates. Our findings demonstrate a dose–response relationship between infectious burden, pelvic adhesions, and pregnancy rates, as well as clinically meaningful trends for endocrine disorders. These observations highlight a significant gap in literature and justify future prospective, multicenter studies with larger cohorts and comparative IVF arms to refine patient selection algorithms and optimize fertility outcomes.

Few studies have evaluated how the cumulative effect of infectious and endocrine comorbidities modifies reproductive prognosis after tubal reconstruction. Moreover, comparative data with IVF-treated populations are lacking. Future multi-center prospective trials should address this gap to refine patient selection and optimize reproductive counseling.

Shifting from a purely anatomical model of hydrosalpinx to an integrative, comorbidity-informed framework may improve individualized counseling, patient stratification, and clinical decision-making, ultimately enhancing reproductive success rates after tubal surgery.

Conclusions

Hydrosalpinx severity emerged as the primary determinant of reproductive prognosis after Palmer-type neosalpingostomy. Endocrine and infectious comorbidities, particularly PCOS, PID, and UTI, were associated with clinically relevant delays in time-to-pregnancy, despite not reaching statistical significance in multivariate analyses. These findings support a comprehensive, comorbidity-informed approach to patient management, integrating preoperative optimization of endocrine and infectious conditions to improve surgical outcomes. For patients with advanced disease, salpingectomy followed by IVF may offer better reproductive prospects. Further prospective, multicenter studies are needed to clarify the cumulative impact of comorbidities and refine patient selection and counseling strategies.

Conflict of interests

The authors declare that they have no conflict of interests.