Determining a Treatment Regimen With Optimal Pregnancy Outcomes in Patients With Chronic Endometritis: A Systematic Review and Network Meta‐Analysis

ABSTRACT

Background and Aims

Chronic endometritis (CE) negatively impacts pregnancy outcomes. This study aimed to compare the efficacy of various treatment regimens on pregnancy outcomes in women with CE.

Methods

We performed a systematic review followed by an NMA in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The primary outcome indicator in the network meta‐analysis was the live birth rate, with secondary outcome including clinical pregnancy rate, ongoing pregnancy rate, and early miscarriage rate.

Results

A comprehensive search yielded 2290 articles, of which 24 trials fulfilled the eligibility requirements for inclusion. Out of these, 14 studies were incorporated into the network meta‐analysis to assess the pregnancy outcomes in women with CE. For live birth outcomes, antibiogram‐guided treatment had the largest surface score under the cumulative sorting curve, but the results from the network meta‐analysis indicated that no treatment improve live births in women with CE. The reports on ongoing and clinical pregnancy outcomes revealed significant findings regarding the effectiveness of Doxycycline plus Prednisone and Nitroimidazole plus Quinolones. Specifically, both treatment combinations significantly enhanced the chances of sustained pregnancy (RR = 1.82, 95% CI = 1.12–2.96 and RR = 1.81, 95% CI = 1.03–3.18, respectively) and clinical pregnancy (RR = 1.65, 95% CI = 1.11–2.44 and RR = 1.47, 95% CI = 1.03–2.10, respectively) in women with CE. Conversely, other treatment options failed to demonstrate any improvement in sustained pregnancy and clinical pregnancy outcomes. In the report focusing on early miscarriage outcomes, none of the treatments examined showed a statistically significant reduction in the rate of miscarriage.

Conclusion

Current evidence from this network meta‐analysis does not demonstrate that any single antibiotic regimen significantly improves live birth rates in women with CE. While secondary outcome analyses suggest potential benefits of combining antibiotics with prednisone or specific dual‐antibiotic regimens for clinical and ongoing pregnancy rates, these exploratory findings require cautious interpretation and validation through large‐scale RCTs.

1. Introduction

Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium. It is pathologically characterized by plasma cell infiltration into the endometrial stroma, frequently accompanied by stromal edema and inflammatory cell infiltrates. This chronic inflammation disrupts normal endometrial functions, thereby impairing endometrial receptivity and adversely affecting reproductive outcomes [1]. It has been extensively investigated in the field of reproduction owing to its adverse effects on pregnancy outcomes, including predisposition to infertility, repeated implantation failures, and recurrent abortion [2]. Patients with CE have a 60% higher risk of infertility, unlike their counterparts of normal reproductive age [3].

Antibiotics are commonly used to treat CE because they can relieve local inflammation. Previous reports have shown the rate of CE endometrial histological cure of 66% to 93% after antibiotic treatment [4, 5, 6]. Nevertheless, the effect on pregnancy outcomes is the major concern of most patients with CE in reproductive medicine. However, several relevant meta‐analyses have shown that the evidence regarding the improvement of pregnancy outcomes in CE patients with antibiotic therapy is inconsistent. These meta‐analyses have primarily compared the overall outcomes between treated and untreated patients, or between those who were cured and those who were not. These studies have not specifically examined the effectiveness of different treatment approaches [7, 8]. Unlike conventional traditional pairwise meta‐analyses, network meta‐analysis provides more accurate estimates, and can rank interventions to guide clinical decisions [7]. Various combinations of CE treatment protocols are currently emerging causing confusion among clinicians may experience confusion when selecting among CE treatment interventions [9]. Therefore, it is important to identify effective treatments for CE. A systematic review and network meta‐analysis were carried out to compare the efficacy of various treatment regimens on pregnancy outcomes in CE patients. This review aims to identify specific and effective assisted reproductive techniques for CE to inform clinical practice. This study aims to compare the effects of different treatments on pregnancy outcomes in women with CE.

2. Materials and Methods

2.1. Search Strategy and Selection Criteria

This meta‐analysis complied with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement [10, 11]. We have registered the protocol for this study in the International Prospective Register of Systematic Reviews database (CRD 42024538159). Electronic databases (Pubmed, Cochrane Library, Web of Science, Embase) were searched up to April 30, 2025. The search was restricted to human studies. The authors (Z.G. and Y.Q.) assessed the electronic search and study eligibility. A manual search was conducted to comprehensively capture relevant publications in the reference lists of key articles. For the same team's publications across different periods, we contacted the corresponding author to ensure that all included studies are based on independent patient populations. Appendix 1 presents the details of the search strategy.

Regardless of the investigators' disciplinary background or the clinical setting, the diagnosis of CE in all included studies was consistently based on internationally recognized histopathological standards, primarily the immunohistochemical identification of CD138+ plasma cells in the endometrial stroma.

The clinical studies were included to compare two or more treatment options among patients diagnosed with CE prior to conception or embryo transfer. The diagnosis of CE in all included studies was consistently based on internationally recognized histopathological standards, primarily the identification of plasma cells in the endometrial stroma [12]. Studies were excluded when they met the criteria as follows: a single‐arm trial, or a study that only compared pregnancy outcomes between CE and non‐CE groups.

The treatment regimen includes various types of medications or no medication. In drug regimens where antimicrobial susceptibility testing guides treatment, specific pathogens are primarily identified through microbial culture of endometrial tissue, and appropriate antibiotics are selected based on the drug susceptibility results.

2.2. Data Extraction and Assessment of Risk of Bias

Two researchers (Z.G. and Y.Q.) independently performed the literature search and selected the studies. All available data on study characteristics and outcomes were collected and extracted by the reviewers (O.P. and Y.C.). The following variables were retrieved from the studies: country, year, study type, duration, sample size, specific drug dosage, and treatment frequency for each study. Outcome indicators included pregnancy outcomes such as live births (Women resulting in the delivery of at least one live‐born infant), cumulative live births (Successful live birth after fresh embryo transfer or frozen embryo transfer in patients undergoing assisted reproductive treatment within 2 years after ovulation induction), ongoing pregnancies (Pregnancies confirmed by ultrasound that continue beyond 12 weeks of gestation with fetal cardiac activity), clinical pregnancies (Pregnant women with an intrauterine gestational sac detected by ultrasound), biochemical pregnancies (Women with a positive serum or urine hCG test), embryo implantation (Transferred embryos that develop into detectable gestational sacs on ultrasound), ectopic pregnancies (Clinical pregnancies implanted outside the uterine cavity by ultrasound), early miscarriages (Clinically recognized pregnancies lost spontaneously at or before 12 weeks of gestation), late miscarriages (Pregnancies lost spontaneously between ≥ 12 weeks and < 28 weeks of gestation), and preterm births (Live births occurring at ≥ 28 weeks but before 37 completed weeks of gestation). For the network meta‐analysis, the primary outcome was live birth rate whereas secondary outcomes were clinical pregnancy rate, ongoing pregnancy rate, and early miscarriage rate.

Two reviewers (Z.G. and Y.Q.) independently assessed the methodological quality of the included studies that used the modified version of the “Newcastle‐Ottawa Scale” [7, 13]. The quality of studies was evaluated across 5 domains, with specific details provided in Appendix 2. Each study was classified as having a low risk of bias (≥ 3 points) or a high risk of bias (< 3points) based on the total points assigned. Disagreements were resolved by a third independent reviewer (T.X.), who was blinded to the primary data extraction process and acted solely as an objective adjudicator.

2.3. Data Synthesis

A meta‐analysis was carried out to simultaneously compare 10 treatment options for CE, evaluating live birth, ongoing pregnancy, clinical pregnancy, and early miscarriage outcomes. Network plots were created to visualize the structural network [14]. Considering that endometrial pathology testing in all CE patients requires endometrial scratch surgery, surgical treatment, and no treatment were categorized as the same node in network meta‐analysis. Similarly, drugs within the same class were grouped as nodes in the analysis: Levofloxacin and ciprofloxacin as quinolones, metronidazole and tinidazole as nitroimidazoles. A treatment interaction test was performed to evaluate network inconsistency [15]. Direct and indirect comparisons between treatments were investigated through a pairwise meta‐analyses based on the random effects model. In the network meta‐analysis, summary treatment effects (relative risk ratios [RRs]), with corresponding 95% confidence intervals (CIs) were calculated for each intervention as compared with no treatment. Comparing medicated cohorts with untreated patients is an essential prerequisite in this network, as it establishes a baseline to quantify the absolute clinical benefit of pharmacological interventions over the natural disease course. Treatments were ranked using the surface under the cumulative ranking curve [7, 15].

All statistical analyses for the network meta‐analysis were conducted using the frequentist approach with the ‘netmeta’ package (version 2.4‐0) in R software (version 4.3.3). Pairwise comparisons between treatments were performed using a random‐effects model. The primary outcome was live birth rate, and secondary outcomes included clinical pregnancy rate, ongoing pregnancy rate, and early miscarriage rate. To evaluate the presence of statistical inconsistency in the network, we performed both global and local inconsistency assessments. Global inconsistency was examined using the design‐by‐treatment interaction model within a frequentist framework. Local inconsistency for specific comparisons with available direct and indirect evidence was assessed using node‐splitting analysis. For all analyses, relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated. A two‐sided p‐value < 0.05 was considered statistically significant.

3. Results

3.1. Study Selection and Study Characteristics

The literature search, identification, and selection protocol are shown by the flowchart in Figure 1. A total of 2290 articles were screened and 24 trials met the eligibility criteria. In total, 14 studies were included in the network meta‐analysis. Table 1 shows the key characteristics of these trials, which were conducted across nine countries and reported in English.

Figure 1.

The Flowchart of showing the selection of clinical studies comparing fertility‐assisted treatment in patients with chronic endometritis.

Table 1.

General features of the included studies.

Author, year, country	Study design	Period	Sample size	Inclusion criteria	Drug, dosage, frequency, time	Outcome measures
Cicinelli et‐al. 2014, Italy [16]	Cohort study	Jan 2008 to Jan 2011	142 vs 66	RPL patients with CE	a. Antibiogram‐guided treatment b. Ceftriaxone, 250 mg+Doxycycline, 100 mg+Metronidazole, 500 mg, Bid, 14 days	④
Yang et‐al. 2014, China [17]	Cohort study	Jan 2009 to Apr 2012	109 vs 47	RIF patients with CE	a. Levoflfloxacin, 500 mg+Metronidazole, 1000 mg, Qd, 14 days b. No treatment	③④⑥
McQueen et‐al. 2014, USA [18]	Cohort study	Jul 2004 to Feb 2012	26 vs 9	RPL patients with CE	a. Oflfloxacin, 400 mg+Metronidazole, 500 mg, Bid,14 days b. Doxycycline/Doxycycline+Metronidazole/Ciproflfloxacin+Metronidazole	①
Chattopadhyay et‐al. 2017, USA [19]	Cohort study	2011 to 2016	67 vs 584	Failed euploid FET patients with CE	a. Empiric antibiotics, throughout the FET cycle b. No treatment	③⑧
Kuroda et‐al. 2020, Japan [20]	Cohort study	Jun 2018 to Feb 2020	29 vs 18	CE patients	a. Antibiogram‐guided treatment, 14 days b. No treatment	③④⑤⑧
Nomiyama et‐al. 2021, Japan [21]	Cohort study	Jul 2017 to Oct 2019	25 vs 24	Infertility patients with CE	a. Operative treatment b. (a)+Doxycycline, 100 mg, Bid, 14 days	④
Pantos et‐al. 2021, Greece [22]	Randomized controlled trial	Mar 2017 to Feb 2019	40 vs 40	RIF or RPL patients with CE	a. Doxycycline, 100 mg, Bid+Metronidazole, 500 mg, Bid, 14 days b. (a)+Ciprofloxacin solution (200 mg/100 mL) 1 infusion every 3 days, 30 days	①④
Xiong et‐al. 2021, China [23]	Cohort study	Jun 2017 to Jun 2018	346 vs 60 vs 116	Infertility patients with CE	a. Doxycycline, 100 mg, Bid, 14 days b. (a)+Levoflfloxacin, 200 mg, Bid+Metronidazole, 500 mg, Tid, 14 days/28 days c. No treatment	①②④⑥⑧
Mitter et‐al. 2021, Switzerland [24]	Cohort study	Jan 2014 to Dec 2018	41 vs 1	RIF or RPL patients with CE	a. Doxycycline, 100 mg, Bid, 14 days b. Ciprofloxacin, 400 mg, Qd, 14 days	①④
Song et‐al. 2021, China [6]	Randomized controlled trial	2016 to 2018	60 vs 60	CE patients	a. Levoflfloxacin, 500 mg+Tinidazole, 1000 mg, Qd, 14 days b. No treatment	③⑥⑧
Kuroda et‐al. 2021, Japan [25]	Cohort study	Mar 2019 to Mar 2020	62 vs 160	Infertility patients with CE	a. Doxycycline, 100 mg, Bid b. (a)+Operative treatment	④⑧
Gay et‐al. 2021, France [26]	Cohort study	Jan 2013 to Jan 2018	13 vs 9	RPL patients with CE	a. Antibiogram‐guided treatment, 14 days b. No treatment	①⑧
Barinov et‐al. 2021, Russia [27]	Randomized controlled trial	/	23 vs 47	CE patients	a. Antibiogram‐guided treatment b. (a)+Modified polyvinylpyrrolidone	④
Zou et‐al. 2022, China [28]	Cohort study	Jun 2020 to Nov 2021	55 vs 45 vs 28	RIF patients with CE	a. Doxycycline, 100 mg, Bid, 14 days b. (a)+Prednisone, 5 mg, Qd, 14 days c. No treatment	③④⑤⑥⑦⑧
Liu et‐al. 2022, China [29]	Cohort study	Mar 2018 to Jan 2020	927 vs 334 vs2742	Infertility patients with CE	a. Doxycycline, 100 mg, Bid, 14 days b. (a)+Levoflfloxacin, 200 mg, Bid+Metronidazole,500 mg, Tid, 14 days c. No treatment	①③④⑥⑦⑧⑨
Giulini et‐al. 2022, Italy [30]	Cohort study	2019 to 2020	13 vs 14	RIF patients with CE	a. Prednisone, 10 mg, Qd+Doxycycline, 100 mg, Bid, 14 days b. Prednisone, 10 mg, Qd	①④⑤⑧
Kuroda et‐al. 2022, Japan [31]	Cohort study	Nov 2018 to Jun 2021	199 vs 34	CE patients	a. Operative treatment b. (a)+Antibiogram‐guided treatmen, 14 days	④⑧
Xiang et‐al. 2022, China [32]	Cohort study	Jul 2016 to Jul 2018	59 vs 55	CE patients	a. Levofloxacin, 500 mg+Tinidazole, 1000 mg, Qd, 14 days b. No treatment	①⑤⑦⑧⑨⑩
Liu et‐al. 2022, China [33]	Cohort study	Jun 2018 to Dec 2021	165 vs 327	Infertile patients with CE	a. Clarithromycin, 750 mg/Levofloxacin, 400 mg, Qd, 7 days b. (a)+Doxycycline, 100 mg/Levofloxacin, 200 mg+Metronidazole, 400 mg, Bid, 14 days	①③④⑧⑩
HogenEsc et‐al. 2023, USA [34]	Cohort study	Jan 2014 to Dec 2020	129 vs 18	CE patients	a. Empiric antibiotic therapy b. No treatment	①
Kuroda et‐al. 2023, Japan [35]	Cohort study	Jan 2019 to Jun 2021	51 vs 15	Infertile patients with CE	a. Dilation and curettage b. No treatment	③④⑧
Vaduva et‐al. 2023, Romania [36]	Cohort study	2018 to 2021	148 vs 44	Infertile patients with CE	a. Quinolones and Nitroimidazole, Bid, 14 days b. No treatment	④
Ma et‐al. 2023, China [37]	Cohort study	Jul 2019 to Jun 2021	20 vs 22	RIF patients with CE	a. Doxycycline,100 mg, Bid+Metronidazole,400 mg, Bid, 14 days b. (a) +Intrauterine infusion gentamicin, 80 mg+ dexamethasone, 5 mg	①③④⑥⑦⑩
Ping Hu et‐al. 2024, China [38]	Cohort study	July 2021 to August 2022	119 vs 135	CE patients	a. Doxycycline, 100 mg, Bid, 14 days b. (a) +Probiotics, 0.25 g, Qd, 10 days	①④⑤⑦⑩

Note: Outcome measures: ① Live birth rate: The proportion of women/cycles resulting in the delivery of at least one live‐born infant; ② Cumulative live birth rate: The probability of successful live birth after fresh embryo transfer and frozen embryo transfer in patients undergoing assisted reproductive treatment within 2 years after ovulation induction; ③ Ongoing pregnancy rate: The proportion of pregnancies confirmed by ultrasound that continue beyond 12 weeks of gestation with fetal cardiac activity; ④ Clinical pregnancy rate: The proportion of cycles with an intrauterine gestational sac detected by ultrasound; ⑤ Biochemical pregnancy rate: The proportion of cycles with a positive serum or urine hCG test; ⑥ Implantation rate: The proportion of transferred embryos that develop into detectable gestational sacs on ultrasound; ⑦ Ectopic pregnancy rate: The proportion of clinical pregnancies implanted outside the uterine cavity by ultrasound; ⑧ Early miscarriage rate: The proportion of clinically recognized pregnancies lost spontaneously at or before 12 weeks of gestation; ⑨ Late miscarriage rate: The proportion of pregnancies lost spontaneously between ≥ 12 weeks and < 28 weeks of gestation; ⑩ Preterm birth rate: The proportion of live births occurring at ≥ 28 weeks but before 37 completed weeks of gestation.

Table 2 details the dosage and frequency of each treatment regimen. The 14 trials compared at least 2 of the 10 treatment regimens or their combinations: glucocorticoid, doxycycline, doxycycline plus Glucocorticoid, Doxycycline plus nitroimidazole plus dexamethasone plus gentamicin, antibiogram‐guided treatment, doxycycline plus nitroimidazole, doxycycline plus nitroimidazole plus quinolones, nitroimidazole plus quinolones, doxycycline plus probiotics and no treatment.

Table 2.

The dosage and frequency of use of all single treatment regimens.

Treatment	Dosage, frequency, time, delivery	Source
Tetracycline
Doxycycline	100 mg, Bid, 14 days, p.o.	[19, 20, 21, 22, 23, 24, 25, 27, 28, 31, 32, 36, 37]
Nitroimidazole
Metronidazole	500 mg, Bid, 14 days, p.o./ 400 mg, Bid, 14 days, p.o./ 1000 mg, Qd, 14 days, p.o./ 500 mg, Tid, 14 days/28 days, p.o.	[15, 21, 22, 25, 28, 32, 36]
Tinidazole	1000 mg, Qd, 14 days, p.o.	[6, 31]
Quinolones
Levoflfloxacin	500 mg, Qd, 14 days, p.o./ 400 mg, Qd, 7 days, p.o./ 200 mg, Bid, 14 days/28 days, p.o.	[6, 16, 22, 28, 32]
Oflfloxacin	400 mg, Bid, 14 days, p.o.	[17]
Ciproflfloxacin	400 mg, Qd, 14 days, p.o./ 200 mg, Intrauterine infusion	[17, 21, 23]
Glucocorticoid
Prednisone	10 mg, Qd, 14 days, p.o./ 5 mg, Qd, 14 days, p.o.	[27, 29]
Dexamethasone	5 mg, Intrauterine infusion	[36]
Cephalosporins
Ceftriaxone	250 mg, Bid, 14 days, p.o.	[15]
Macrolides
Clarithromycin	750 mg, Qd, 7 days, p.o.	[32]
Aminoglycosides
Gentamicin	80 mg, Intrauterine infusion	[36]

The following treatment measures were excluded from the network meta‐analysis due to the absence of common control measures: ceftriaxone plus doxycycline plus metronidazole, doxycycline plus metronidazole, ciproflfloxacin plus metronidazole, ciprofloxacin, modified polyvinylpyrrolidone plus antibiogram‐guided treatment, clarithromycin, levofloxacin, quinolones plus doxycycline, clarithromycin plus doxycycline, clarithromycin plus levofloxacin plus metronidazole.

3.2. Risk of Bias of Included Studies

3.2.1. Sample Representativeness

14 studies had a low risk of bias based on the modified Newcastle‐Ottawa Scale, whereas the remaining studies had a high risk of bias.

3.2.2. Sampling Technique

Only four studies adopted adequate random or continuous sampling methods, whereas the remaining studies lacked sufficient data on their sampling techniques.

3.2.3. Ascertainment of CE Diagnosis

All studies documented the rationale for diagnosing CE and had a low risk of bias based on the modified Newcastle‐Ottawa Scale.

3.2.4. Quality of Study Population Description

Three studies lacked specific baseline information, resulting in a high risk of bias. However, other studies provided adequate details.

3.2.5. Incomplete Outcome Data

All studies reported outcomes with a low risk of bias based on the modified Newcastle‐Ottawa Scale.

In summary, based on the modified Newcastle‐Ottawa Scale scoring threshold, all included studies were categorized as having a low risk of reporting bias (Table 3). However, this rating primarily reflects compliance with basic reporting criteria, whereas intrinsic methodological limitations, such as small sample sizes and retrospective cohort designs, remained common across the majority of included studies.

Table 3.

Authors' judgement of study quality according to the “Modified Newcastle‐Ottawa Risk of Bias Scoring System.” [7, 12].

Authors and year (reference)	Year	Sample representativeness	Sampling technique	Ascertainment of CE diagnosis	Quality of description of the population	Total score	Risk of bias
Cicinelli et‐al. 2014, Italy [16]	2014	★	—	★	★	★★★★	Low
Yang et‐al. 2014, China [17]	2014	★	—	★	★	★★★★	Low
McQueen et‐al. 2014, USA [18]	2014	—	—	★	★	★★★	Low
Chattopadhyay et‐al. 2017, USA [19]	2017	★	—	★	—	★★★	Low
Kuroda et‐al. 2020, Japan [20]	2020	—	—	★	★	★★★	Low
Nomiyama et‐al. 2021, Japan [21]	2021	—	—	★	★	★★★	Low
Pantos et‐al. 2021, Greece [22]	2021	—	★	★	★	★★★★	Low
Xiong et‐al. 2021, China [23]	2021	★	—	★	★	★★★★	Low
Mitter et‐al. 2021, Switzerland [24]	2021	—	—	★	★	★★★	Low
Song et‐al. 2021, China [6]	2021	★	★	★	★	★★★★★	Low
Kuroda et‐al. 2021, Japan [25]	2021	★	—	★	★	★★★★	Low
Gay et‐al. 2021, France [26]	2021	—	—	★	★	★★★	Low
Barinov et‐al. 2021, Russia [27]	2021	—	★	★	★	★★★★	Low
Zou et‐al. 2022, China [28]	2022	★	—	★	★	★★★★	Low
Liu et‐al. 2022, China [29]	2022	★	—	★	★	★★★★	Low
Giulini et‐al. 2022, Italy [30]	2022	—	—	★	★	★★★	Low
Kuroda et‐al. 2022, Japan [31]	2022	★	—	★	★	★★★★	Low
Xiang et‐al. 2022, China [32]	2022	★	—	★	★	★★★★	Low
Liu et‐al. 2022, China [33]	2022	★	—	★	★	★★★★	Low
HogenEsc et‐al. 2023, USA [34]	2023	★	—	★	★	★★★★	Low
Kuroda et‐al. 2023, Japan [35]	2023	—	—	★	★	★★★	Low
Vaduva et‐al. 2023, Romania [36]	2023	★	—	★	—	★★★	Low
Ma et‐al. 2023, China [37]	2023	—	—	★	★	★★★	Low
Ping Hu et‐al. 2024, China [38]	2024	★	★	★	★	★★★★★	Low

3.3. Synthesis of Results

A total of 7922 women diagnosed with CE were allocated to 10 different treatment regimens. The forest plots comparing outcomes are illustrated in Figure 2 and network plots for all outcomes are presented in Appendix 3.

Figure 2.

Forest plot showing the results of the network meta‐analysis. Reference treatment: No treatment. (A) The live birth outcome; (B) The ongoing pregnancy outcome; (C) The clinical pregnancy outcome; (D) The early miscarriage outcome.

Five different drug combinations were analyzed from six clinical trials to determine their impact on live birth rates. It was observed that no measures taken can improve live births in women with CE (Figures 2A and 3A).

Figure 3.

The network plots for all outcomes (A) The live birth outcome; (B) The ongoing pregnancy outcome; (C) The clinical pregnancy outcome; (D) The early miscarriage outcome.

Further, four prescribing combinations were analyzed in the report on ongoing pregnancy outcomes report across six clinical studies. Consequently, doxycycline plus prednisone and nitroimidazole plus quinolones significantly increased the likelihood of sustained pregnancy compared to no treatment (RR = 1.82, 95% Cl = 1.12–2.96; RR = 1.81, 95% Cl = 1.03–3.18, respectively). However, doxycycline alone and doxycycline plus nitroimidazole did not improve ongoing pregnancy rates in women with CE (Figures 2B and 3B).

A total of nine formulation combinations were analyzed in the report on clinical pregnancy outcomes across 13 clinical studies. doxycycline plus prednisone and nitroimidazole plus quinolones significantly increased the likelihood of clinical pregnancy compared to no treatment (RR = 1.65, 95% Cl = 1.11–2.44; RR = 1.47, 95% Cl = 1.03–2.10, respectively). Other treatment options did not improve clinical pregnancies in women with CE (Figures 2C and 3C).

In total, five formulation combinations were analyzed in the report on early miscarriage outcomes across eight clinical studies. None of the treatments demonstrated a significant effect in reducing the miscarriage rate (Figures 2D and 3D).

Inconsistency tests found no evidence of either global or local inconsistencies (Appendix 4). Treatment rankings were based on the area under the cumulative ranking curve (Appendix 5), where the effect of each intervention was quantified as a percentage. Treatments with a higher area under the cumulative ranking curve were considered more effective. Based on the result of area under the cumulative ranking curve(Appendix 5), antibiogram‐guided treatment ranked highest for live birth; however, pair‐wise and network comparisons showed no statistically significant differences among any of the evaluated regimens, indicating that these numerical rankings should be interpreted with caution. In terms of early abortion, the Antibiogram‐guided treatment ranked high in numerical probability to nitroimidazole plus quinolone, doxycycline plus prednisone, doxycycline alone, and doxycycline plus nitroimidazole plus quinolone.

4. Discussion

4.1. Principal Findings

In this network meta‐analysis, no treatment regimen demonstrated a statistically significant improvement in the primary outcome of live birth rate. However, regarding secondary outcomes, combination therapy of doxycycline plus prednisone and nitroimidazole plus quinolones showed statistically significant increases in clinical and ongoing pregnancy rates compared to no treatment. Among antibiotic regimens, nitroimidazole and quinolones combination showed statistically significant relative increases in clinical and ongoing pregnancy rates compared with no treatment. Conversely, none of the other antibiotic regimens showed significant benefits for pregnancy. The different antibiotic treatments, patient characteristics, and bacterial resistance patterns can lead to different outcomes in patients with CE. This complexity makes it challenging to predict the best treatment approach for each individual patient and highlights the importance of further research to optimize treatment strategies. These complexities contribute to the inconsistent results obtained in previous meta‐analyses on the efficacy of antibiotic therapy on pregnancy outcomes in patients with CE.

4.2. Comparison With Existing Literature

As described in current literature, the prevailing treatment approach for CE entails administering empirical oral antibiotics, towards eliminating the underlying bacterial infection. Our findings indicate that among all antibiotic regimens, the combination of nitroimidazole and quinolones is the most effective in improving clinical and sustained pregnancy rates among patients with CE. Nitroimidazoles and quinolones are highly complementary in their antimicrobial spectrum and may cover several pathogenic microorganisms. The combined antimicrobial spectrum of nitroimidazoles and quinolones might contribute to more comprehensive pathogen coverage, which could theoretically support better endometrial clearance and, consequently, improved pregnancy outcomes. However, the efficacy of different antibiotic regimens in the management of CE appears to be inconsistent. For instance, our analysis found that the triple combination of doxycycline, nitroimidazole, and quinolones did not demonstrate a significant benefit for pregnancy outcomes. The reasons for this lack of efficacy warrant further investigation. Additionally, overuse of antibiotics inhibits protein synthesis in pathogenic bacteria and affects the protein synthesis in normal intestinal flora. This dual action eliminates harmful bacteria but can also disrupt the balance of beneficial bacteria, potentially leading to dysbiosis in the uterine cavity [39]. Taken together, these findings highlight the complexity of CE management and suggest that a one‐size‐fits‐all antibiotic approach may be insufficient. While promising signals were observed for certain combination regimens or targeted antibiotic treatment, robust confirmation through adequately powered randomized controlled trials is still needed.

Clinically, CE differs from acute endometrial inflammation by its chronic nature, characterized by a prolonged duration. CE is often asymptomatic or presents with non‐specific symptoms such as abnormal uterine bleeding, pelvic pain, or discharge [40, 41]. This condition presents with a slow progression and a multifactorial etiology. The etiology of CE is multifactorial, encompassing infectious agents including bacteria, viruses, and possibly fungi, as well as non‐infectious stimuli including retained gestational tissue or chronic irritation from intrauterine devices [42]. These agents provoke a persistent but dysregulated immune response within the endometrial microenvironment. Pathophysiologically, CE represents a persistent dysregulated endometrial immunological state rather than a simple transient infection. Bacterial pathogens trigger localized inflammatory cascades through pattern recognition receptors, promoting ectopic B‐cell recruitment and stromal plasma cell infiltration [43, 44]. Concurrently, CE induces skewed T‐cell polarization and elevated pro‐inflammatory cytokine expression, which impairs local Treg function and disrupts immune‐stromal communication [45, 46]. This localized persistent inflammation impairs endometrial energy metabolism and receptivity, creating a hostile microenvironment for embryo implantation and early pregnancy maintenance [47].

Prednisone is the most commonly used glucocorticoid in the reproductive medicine field because of its dual immunomodulatory and anti‐inflammatory properties [48]. Prednisone exert anti‐inflammatory and immunomodulatory effects by suppressing NF‐κB‐driven pro‐inflammatory cytokines and restoring the uterine Th17/Treg balance, thereby fostering maternal‐fetal immune tolerance [49, 50]. Therefore, combining hormonal therapy, particularly glucocorticosteroids, with antibiotics is a optimizing strategy to improve fertility. Our finding that doxycycline plus prednisone significantly improved clinical and ongoing pregnancy rates supports the concept that combining anti‐inflammatory immunomodulation with pathogen clearance is more effective than antimicrobial therapy alone.

4.3. Strengths and Limitations

For the first time, this network meta‐analysis sought to evaluate and compare treatment modalities for CE pregnancy outcomes. It integrates different spectrum of treatment modalities for CE through indirect comparisons, hence providing a systematic and holistic appraisal of their comparative efficacy. The work also provides the comprehensive summary of current treatment options for patients with CE.

Nonetheless, the study has several limitations. Firstly, only six subsets of included studies reported live birth outcomes, resulting in limited statistical power and wide confidence intervals. Consequently, no intervention showed a statistically significant benefit for the primary outcome of live birth, which represents a major constraint of the current evidence base. Furthermore, substantial clinical heterogeneity across the included literature represents aanother limitation of this synthesis. The included trials exhibited considerable diversity across patient populations, therapeutic interventions and reproductive settings. From a methodological standpoint, combining such diverse cohorts could potentially challenge the transitivity assumption required for indirect network comparisons. Clinicians must interpret indirect treatment comparisons and the result of area under the cumulative ranking curve rankings with appropriate caution, recognizing that optimal therapeutic choices may vary according to specific patient phenotypes and clinical settings.

Moreover, the limited number of randomized controlled trials on CE contributes to the overall low level of evidence, hindering definitive conclusions. Furthermore, interventions involving assisted reproductive technology could not be included in this network meta‐analysis due to the lack of shared comparators among the included studies. The specific correlation between CE resolution and pregnancy outcomes could not be determined due to limited studies reporting both CE clearance rates and pregnancy outcomes. Eventually, this review only covered studies reported in English with a paucity of non‐English reported research findings.

5. Conclusions and Implications

In conclusion, Current evidence from this network meta‐analysis does not demonstrate that any single antibiotic regimen significantly improves live birth rates in women with CE. While secondary outcome analyses suggest potential benefits of combining antibiotics with prednisone or specific dual‐antibiotic regimens for clinical and ongoing pregnancy rates.

In future research, high‐quality, large‐scale randomized controlled trials stratified by reproductive clinical indication are warranted to further refine these findings, especially in improving live birth rate among patients with CE. Moreover, regimen combination should be refined and optimized, ensuring a more targeted and potentially more effective approach to treatment. Long‐term follow‐up studies are important to assess the sustained effects of combination treatment on pregnancy outcomes and offspring health, thereby providing a comprehensive understanding of the benefits and potential risks linked to this treatment modality.

Author Contributions

Zheng Gong: investigation, software, visualization, writing – original draft. Yun‐huan Qiu: investigation. Xiaoli Zhao: writing – review and editing. Oiyie Pang: data curation, conceptualization. Yingqin Cao: methodology. Jumei Shi: project administration. Mengran Lang: project administration. Tian Xia: funding acquisition, writing – review and editing.

Ethics Statement

This study is a systematic review and network meta‐analysis based on previously published clinical trials. No original individual patient data were collected, and no new clinical interventions were performed directly on human participants or animals for this study. Therefore, ethical approval and formal informed consent from participants were not required for this secondary analysis.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

Tian Xia affirms that this manuscript is an honest, accurate, and transparent account of the study being reported.

Supporting information

Supporting File

Gong Z., Qiu Y.‐h., Zhao X., et al., “Determining a Treatment Regimen With Optimal Pregnancy Outcomes in Patients With Chronic Endometritis: A Systematic Review and Network Meta‐Analysis,” Health Science Reports 9 (2026): e73324, 10.1002/hsr2.73324.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. All data synthesized in this systematic review and network meta‐analysis were extracted from publicly available published studies and are included within the article and its supplementary files. The extracted data and R analysis scripts are available from the corresponding author upon reasonable request.