This study aimed to address the clinical challenge of persistent endometritis after doxycycline treatment by conducting a comprehensive analysis and comparison of therapeutic effects between intrauterine PRP perfusion and repeated doxycycline administration. Specifically, the research focused on evaluating the pregnancy outcomes of FET following these two treatment strategies, including biochemical pregnancy rate, clinical pregnancy rate, early miscarriage rate, and live birth rate. The ultimate goals were to verify the effectiveness of PRP in treating endometritis, clarify the advantages of combining PRP with doxycycline over doxycycline monotherapy, and establish a safe, effective, and evidence-based clinical protocol for the management of endometritis, thereby improving the reproductive prognosis of infertile patients with this condition.

A retrospective cohort study design was adopted, with data collected from 1045 infertile patients who underwent routine hysteroscopic endometrial biopsy prior to in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) at Qingdao Women and Children's Hospital and Reproductive Hospital Affiliated to Shandong University between January 2020 and December 2021. The key diagnostic criterion for endometritis was positive immunohistochemical staining for CD138, a specific marker for plasma cells whose presence in the endometrium indicates active inflammation.

Patients were stratified into four groups based on diagnostic results and treatment strategies: 1. Control group: Patients with negative CD138 staining (no endometritis) who received no specific anti-inflammatory treatment. 2. Endometrial negative group: Patients initially diagnosed with endometritis via CD138 positivity, treated with a standard course of oral doxycycline hydrochloride (100 mg twice daily for 14 days), and confirmed to have resolved inflammation (CD138 negative) on follow-up hysteroscopy. 3. Doxycycline + PRP intrauterine perfusion group: Patients with persistent endometritis (CD138 positive after initial doxycycline treatment) who opted for combined therapy, including a second course of oral doxycycline and intrauterine PRP perfusion (prepared from the patient’s autologous blood, concentrated to a platelet count 3-5 times that of peripheral blood, and infused under hysteroscopic guidance 3–5 days before embryo transfer). 4. Doxycycline re-treatment group: Patients with persistent endometritis who received only repeated oral doxycycline treatment (same dosage and duration as the initial course) based on clinical recommendations and personal preferences.

After completing the assigned treatment, all patients underwent endometrial preparation using either natural ovulation cycles (monitoring follicular development until ovulation, followed by FET 3–5 days later) or hormone replacement cycles (administering estrogen to promote endometrial growth, adding progesterone to transform the endometrium, and scheduling FET when the endometrial thickness reached ≥8 mm). The primary outcome measures included biochemical pregnancy rate (positive serum β-hCG 14 days after transfer), clinical pregnancy rate (confirmation of an intrauterine gestational sac via transvaginal ultrasound 4–5 weeks after transfer), early miscarriage rate (loss of pregnancy before 12 weeks of gestation), and live birth rate (delivery of a viable infant at ≥37 weeks of gestation). Baseline clinical characteristics, including age, body mass index (BMI), antral follicle count (AFC), anti-Müllerian hormone (AMH), type of infertility (primary or secondary), duration of infertility, endometrial preparation protocol, endometrial thickness on transfer day, embryo transfer type (cleavage-stage or blastocyst), and number of embryos transferred, were collected and compared across groups. Statistical analyses were performed using SPSS software, with univariate analysis to compare differences between groups and multivariate logistic regression to identify independent factors influencing live birth rate (P < 0.05 was considered statistically significant).

Among the 1045 enrolled patients, 15 canceled embryo transfer due to upper respiratory tract infections or personal reasons, resulting in a final study population of 1030 patients. Of these, 278 were diagnosed with endometritis via CD138 immunohistochemistry, yielding a prevalence rate of 26.99% (278/1030). The distribution of patients across groups was as follows: control group (n=752), endometrial negative group (n=186), doxycycline + PRP intrauterine perfusion group (n=54), and doxycycline re-treatment group (n=38).

Univariate analysis revealed no statistically significant differences between groups in terms of baseline clinical characteristics (P > 0.05). Specifically, the mean age (31.2 ± 4.5 years), BMI (22.3 ± 2.8 kg/m²), AFC (12.5 ± 4.1), AMH (2.8 ± 1.6 ng/mL), proportion of primary infertility (58.2%), mean duration of infertility (3.6 ± 2.1 years), distribution of endometrial preparation protocols (natural cycle: 42.1%, hormone replacement cycle: 57.9%), mean endometrial thickness on transfer day (10.2 ± 1.5 mm), proportion of blastocyst transfer (63.5%), and mean number of embryos transferred (1.8 ± 0.4) were comparable across all four groups, indicating balanced group allocation and eliminating potential confounding factors from baseline characteristics.

In terms of pregnancy outcomes, no significant differences were observed between groups in biochemical pregnancy rate (control group: 56.8%, endometrial negative group: 54.3%, doxycycline + PRP group: 53.7%, doxycycline re-treatment group: 52.6%), clinical pregnancy rate (control group: 48.9%, endometrial negative group: 46.2%, doxycycline + PRP group: 44.4%, doxycycline re-treatment group: 42.1%), or live birth rate (control group: 41.5%, endometrial negative group: 39.2%, doxycycline + PRP group: 37.0%, doxycycline re-treatment group: 34.2%) (all P > 0.05). However, a significant difference was found in the early miscarriage rate: the doxycycline re-treatment group had an early miscarriage rate of 9.09%, which was significantly higher than that of the control group (3.21%) and the doxycycline + PRP intrauterine perfusion group (2.96%) (both P < 0.05). The endometrial negative group had an early miscarriage rate of 3.76%, which was not significantly different from the control group or the doxycycline + PRP group (P > 0.05).

Multivariate logistic regression analysis, adjusting for potential confounding factors such as age, BMI, AMH, and endometrial thickness, confirmed that endometritis was an independent influencing factor for live birth rate (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.51–0.91, P < 0.05). Additionally, combined treatment with PRP and doxycycline was associated with a lower risk of early miscarriage compared to doxycycline monotherapy (OR = 0.32, 95% CI: 0.11–0.93, P < 0.05).

This retrospective cohort study provides valuable clinical evidence that intrauterine PRP perfusion is a promising effective therapeutic strategy for endometritis, particularly in patients with persistent inflammation after initial doxycycline treatment. The combined use of PRP and doxycycline not only achieves comparable biochemical pregnancy, clinical pregnancy, and live birth rates to those of patients without endometritis or with resolved endometritis but also significantly reduces the early miscarriage rate compared to repeated doxycycline monotherapy.

The superior efficacy of the combined therapy may be attributed to the synergistic effects of doxycycline and PRP: doxycycline effectively eliminates pathogenic microorganisms causing endometritis, while PRP delivers a high concentration of growth factors (such as platelet-derived growth factor, transforming growth factor-β, and vascular endothelial growth factor) that promote endometrial epithelial cell proliferation, extracellular matrix remodeling, angiogenesis, and immune regulation. These effects collectively improve endometrial receptivity and create a favorable microenvironment for embryo implantation and early pregnancy maintenance. In contrast, repeated use of doxycycline alone may fail to repair endometrial damage caused by persistent inflammation, leading to a higher risk of early miscarriage.

Furthermore, the study confirms that endometritis is an independent risk factor for reduced live birth rates in FET cycles, emphasizing the importance of timely diagnosis and effective treatment of this condition in infertile patients undergoing ART. The clinical protocol established in this study-combining doxycycline with intrauterine PRP perfusion for persistent endometritis-offers a safe and effective alternative to antibiotic monotherapy, providing new options for optimizing reproductive outcomes in this patient population.

Limitations of this study include its retrospective design, which may introduce selection bias. Future prospective, multi-center, randomized controlled trials with larger sample sizes are needed to further validate the long-term efficacy and safety of PRP-based combined therapy for endometritis.