Protocol for Evaluating The Effect of Pelvic Physiotherapy on Uterine Blood Flow: A Single-Center, Two-Arm, Parallel, Randomized, Clinical Trial.

Infertility is a growing global health concern, affecting an estimated 48 million couples worldwide ( 1 ). According to the World Health Organization (WHO), approximately 17.5% of the global adult population, roughly one in six individuals, experience infertility ( 2 ). Although advances in reproductive medicine have led to effective assisted reproductive technologies (ART), achieving successful natural conception remains challenging due to various causes of infertility. Among ART methods, in vitro fertili zation (IVF) in is a cornerstone of infertility management ( 3 ). However, despite substantial technological progress, implantation after IVF and embryo transfer frequently fails. Studies have shown that nearly 60% of transferred embryos do not implant successfully ( 4 ), and about 10% of women undergoing IVF experience recurrent implantation failure (RIF) ( 3 ). Successful implantation after IVF depends on multiple factors, particularly embryo quality and endometrial receptivity ( 3 ). One of the main determinants of uterine receptivity is the development of the endometrial lining. Evidence suggests that an endometrial thickness greater than 7 mm significantly increases the likelihood of clinical pregnancy ( 5 ). However, the underlying mechanisms regulating endometrial receptivity are not yet fully understood. Previous studies have highlighted the crucial role of both endometrial thickness and uterine artery blood flow in achieving favorable pregnancy outcomes ( 6 ). Increased resistance or impedance in uterine artery flow can reduce endometrial perfusion and impair implantation, especially among patients undergoing assisted reproductive techniques ( 7 , 8 ). Transvaginal color Doppler ultrasound is a reliable method for evaluating uterine perfusion and endometrial receptivity by measuring uterine arterial impedance ( 9 ). Blood flow is commonly assessed using parameters such as the pulsatility index (PI), resistance index (RI), and systolic/diastolic (S/D) ratio, typically during the midluteal phase of the menstrual cycle. During this phase, uterine vascular resistance normally decreases to support implantation; however, persistently elevated resistance has been associated with impaired infertility and adverse pregnancy outcomes ( 8 ). To enhance uterine blood flow and endometrial thickness, several pharmacological treatments, including hormonal agents, anticoagulants, and vasodilators, have demonstrated clinical efficacy ( 6 , 10 , 11 ). In addition, complementary approaches such as traditional East Asian medicine (TEAM) ( 12 ), acupuncture ( 13 ), electroacupuncture ( 14 ), and pelvic physiotherapy ( 15 ) have been explored for their potential benefits. Pelvic physiotherapy, which combines electrotherapy, manual therapy, and targeted exercise programs, may enhance local circulation and improve endometrial development by strengthening pelvic floor muscles ( 15 - 20 ). Nevertheless, evidence on its effectiveness in improving implantation outcomes following IVF remains limited. Various electrical modalities used in pelvic physiotherapy include electrical stimulation, ultrasound therapy, biofeedback, diathermy, and transfer energy capacitive and resistive therapy (TECAR) therapy ( 20 - 22 ). Evidence indicates that biomimetic electrical stimulation can favorably affect endometrial thickness and vascularization in women undergoing IVF by enhancing uterine and sub-endometrial blood flow ( 14 , 20 ). Despite these promoting findings, the potential of pelvic physiotherapy, particularly TECAR therapy, in improving uterine perfusion has not been comprehensively investigated. TECAR therapy is an emerging electrotherapeutic modality that operates within the 300 kHz–1 MHz frequency range. It delivers electromagnetic energy through capacitive and resistive modes, generating deep endogenous heat without external radiant sources ( 23 ). The capacitive mode primarily affects soft tissues with high electrolyte content, whereas, the resistive mode targets denser tissues such as tendons, bones, and joints. Clinical studies have reported that TECAR therapy promotes vasodilation, enhances tissue oxygenation, and improves local blood circulation ( 24 , 25 ). Although its efficacy has demonstrated in certain pelvic floor disorders ( 26 , 27 ), its potential application for improving uterine blood flow or fertility outcomes remains unexplored. Recognizing this research gap, the present protocol has been developed to evaluate the effects of pelvic physiotherapy, including electrotherapy, exercise therapy, and TECAR therapy, on uterine blood flow and fertility outcomes. This study aims to design and implement a randomized clinical trial protocol to assess whether pelvic physiotherapy can improve uterine perfusion in infertile women with RIF. The central hypothesis is that participants receiving pelvic physiotherapy in combination with standard pharmacotherapy will demonstrate greater improvements in uterine blood supply, implantation rate, and pregnancy outcomes compared with those receiving pharmacotherapy alone.

Dissemination of trial results: Upon completion, results will be submitted for publication in a peer-reviewed jour nal and may be presented at international conferences. Authorship eligibility will be determined in accordance with the Vancouver guidelines. The corresponding author will be available for inquiries regarding the study proto col.

This study outlines the design protocol for a trial evaluating the effects of physiotherapy, including electrotherapy, exercise therapy, and TECAR therapy, on women experiencing infertility. The study specifically targets women with high uterine artery resistance. A key strength of this study is its focus on assessing the effectiveness of physiotherapy interventions in improving uterine artery blood flow. These approaches have the potential to be integrated into the clinical management of infertile women with a history of RIFs. Considering the substantial financial costs and emotional distress associated with unsuccessful IVF cycles, any intervention that enhances the likelihood of a successful pregnancy is clinically valuable. Moreover, this project aligns with broader efforts to promote pro-natalist policies and improve reproductive health outcomes.

Given the limited research on the efficacy of pelvic physiotherapy in enhancing uterine blood supply, the findings of this study will provide preliminary insights into the effectiveness of this intervention. The results may guide the development of optimized physiotherapy protocols for infertile women with RIF associated with increased uterine artery resistance.

The present study, describing a clinical trial protocol, has been approved by the Physical Therapy Department of Rehabilitation Faculty of Tabriz University of Medical Sciences. This protocol, developed based on the findings of previous studies, is intended to guide a pilot clinical trial with a minimal number of participants. Participants meeting the inclusion criteria will be enrolled only after providing informed, voluntary consent by signing the designated consent form. Prior to any clinical implementation, the protocol will be submitted for formal approval to the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1402.491). Ethical approval and Iranian Registry of Clinical Trials (IRCT) registration (IRCT20230206057338N1) will be obtained before initiating any participant recruitment or intervention. This single-center, two-arm, parallel, randomized, single-blind clinical trial will be conducted at Al-Zahra Hospital, Tabriz University of Medical Sciences, during 2025-2026. Infertile women with a history of at least two repeated implantation failures who plan to undergo re-implantation via IVF at the infertility clinic will be invited to participate. Volunteers will be assessed by an infertility gynecologist on the first to third days of their menstrual cycle, and transvaginal ultrasound will be performed by a radiologist. Participants will be recruited by the infertility gynecologist based on the following inclusion criteria: age between 28 and 40 years, a history of at least two repeated implantation failures (RIFs), high uterine artery resistance (PI>1.95), regular menstrual cycles (21-35 days), and availability of at least two embryos (grade A or B) for transfer ( 15 , 20 , 28 - 31 ). Individuals will be excluded if they have congenital uterine anomalies, fibroids, severe endometriosis, myomas, adenomyosis, ovarian cysts, severe ovulation disworders, premature ovarian failure, hypothalamic amenorrhea, diabetes, dyslipidemia, smoking, alcohol consumption, vegetarianism, hypertension, coagulation disorders, Asherman’s syndrome, uterine dysplasia, mental illnesses, contraindications to estrogen therapy, anemia, hyperthyroidism, or cardiac, hepatic, or renal complications. Participants whose embryos are not grade A or B after thawing, or whose endometrial thickness is less than 6 mm on the day of endometrial conversion, will also be excluded. Inclusion and exclusion criteria will be assessed by the gynecologist based on the participant medical history and sonography reports ( 11 , 15 , 20 , 30 - 33 ). In the current study, the optimal cut-off value of the uterine artery PI for predicting increased uterine blood flow impedance was > 1.95. At this threshold, sensitivity was 95%, specificity 86.7%, positive predictive value 90.47%, negative predictive value 92.86%, and overall diagnostic accuracy 91.42%. Pharmacotherapy group (control group): Participants will receive 2 mg estradiol tablets, starting with 2 tablets on the second day of the menstrual cycle, followed by 3 tablets daily from the third day onward ( 11 ). Pelvic physiotherapy with pharmacotherapy group (intervention group): In addition to pharmacotherapy, standard pelvic floor physiotherapy treatment, including electrotherapy and pelvic floor exercises, will be administered. Treatments will be provided twice weekly for one menstrual (8-10 sessions over 3-4 weeks, depending on menstrual length) by a certified pelvic physiotherapist. Electrical stimulation will be delivered via a vaginal electrode, with the patient in a supine position with knees bent. Lubricating gel will be applied, and the electrode inserted vaginally. Electrotherapy parameters: internal frequency of 150 Hz, burst frequency 2 Hz, pulse duration 250 ms, and variable amplitude 0-90 mA for 30 minutes. Current intensity will be gradually increased to the patient tolerance threshold ( 17 ). TECAR therapy will involve applying radiofrequency waves via capacitive electrodes at 300 kHz for 20 minutes ( 34 ). The abdomen and sacrum will be covered with a special conductive cream, and a passive metal electrode will be positioned over the sacral region. A monopolar active electrode (0.5 cm diameter) will be moved around the uterus and ovaries by the physiotherapist. Pelvic floor exercises will be taught using a pictorial pamphlet, with weekly progression based on each participant’s ability ( 35 ). Embryo implantation: Following a routine ultrasound on the second or third day of menstruation, hormone replacement therapy (HRT) will be initiated using 2 mg estradiol tablets. The estradiol dose will be adjusted according to standard protocols to achieve an endometrial thickness greater than 7 mm. If endometrial thickness exceeds 7.5 mm, injectable progesterone will be administered at 50 mg (once on the first day, then twice daily). On the fourth day of progesterone administration, luteal phase support will be initiated using 400 mg rectal progesterone suppositories every 12 hours and 50 mg progesterone ampoules every three days. On the day of embryo transfer, an ultrasound will be performed to measure endometrial thickness prior to transfer. Two or three grade A or B embryos at the cleavage stage will then be transferred into the uterus. Post-transfer, patients will continue estradiol and progesterone treatment (800 mg suppositories and 50 mg ampoules) for up to 12 weeks ( 7 , 11 ). Primary outcomes: The primary outcomes include uterine blood supply, assessed via arterial RI, PI, and S/D ratio, endometrial pattern, and endometrial thickness. These parameters will be evaluated using transvaginal ultrasound during the mid-luteal phase of the menstrual cycle, specifically between the fifth and eighth day after ovulation ( Fig .1 ). Uterine blood supply status: The RI, PI, and the (S/D) ratio are established indices for assessing uterine artery blood flow and vascular resistance. Measurements will involve recording between three and ten consecutive waveforms. The peak systolic velocity (PSV) is defined as the highest point of each waveform and is expressed in centimeters per second (cm/s). The end-diastolic velocity (EDV) is also expressed in cm/s. The S/D ratio will be calculated as PSV divided by EDV. The PI will be calculated as the difference between PSV and EDV divided by the mean velocity during the cardiac cycle. The RI will be calculated as the difference between PSV and EDV divided by PSV ( 8 , 9 ). Endometrial thickness: Endometrial thickness will be measured in the sagittal plane as the distance between the thickest echogenic areas of the two basal endometrial interfaces across the endometrial canal ( 36 ). Uterine blood flow assessment using transvaginal color Doppler ultrasound. Key parameters include the resistance index (RI), pulsatility index (PI), and systolic/diastolic (S/D) ratio, which collectively reflect uterine artery perfusion and vascular resistance. Endometrial pattern: Endometrial patterns will be classified into three types: Pattern A: Triple-line pattern, consisting of a central hyperechoic line surrounded by two hypoechoic layers. Pattern B: Intermediate isoechoic pattern, with echogenicity similar to the surrounding myometrium and a poorly defined central line. Pattern C: Homogeneous, hyperechogenic endometri um ( 37 ). um ( 37 ). Secondary outcomes: Secondary outcomes include sexual function, depression, quality of life, pregnancy rate, implantation rate, fetal growth up to the 12 th week, ectopic pregnancy, and miscarriage. Sexual function index: Women’s sexual function will be assessed across multiple domains, including desire, arousal, lubrication, orgasm, satisfaction, and pain. The validated Persian version of the Female Sexual Function Index (FSFI) will be used to evaluate these domains over a 30-day period. The FSFI comprises 19 items and generates a total score, with lower scores indicating greater sexual dysfunction. A score of 26.55 serves as the cutoff for determining sexual dysfunction ( 38 ). Depression rate: Depression in infertile women will be assessed using the validated Persian version of the beck depression inventory (BDI). The BDI comprises 21 items, and the total score reflects the severity of depression: 0-9 indicates no depression, 10-18 mild depression, 19-29 moderate depression, and ≥30 severe depression ( 39 ). Quality of life index: The validated Persian version of the Women’s Sexual Quality of Life Questionnaire (SQOL-F) will be used to evaluate sexual quality of life in infertile women. This questionnaire assesses sexual self-confidence, emotional experiences, and sex-related issues. It consists of 18 items, each with six-point Likert -type responses ranging from strongly agree to strongly disagree. Higher scores indicate better quality of life ( 40 ). Pregnancy rate: Pregnancy rate is defined as the ratio of cycles resulting in pregnancy to the total number embryo transfer cycles. Pregnancy will be assessed using both chemical and clinical methods. Serum beta-human chorionic gonadotropin (β-hCG) levels will be measured 14 days after embryo transfer at the cleavage stage and 12 days after transfer at the blastocyst stage. The chemical pregnancy rate will be calculated as the number of positive β-hCG results (≥ 25 mIU/mL) divided by the total number of transfers. Two weeks after a positive chemical pregnancy test, transvaginal ultrasound will be performed to visualize the uterus, count the number of gestational sacs, and record fetal heart rate. The clinical pregnancy rate will be calculated as the ratio of observed gestational sacs to the number of embryos transferred ( 11 ). Implantation rate: The implantation rate is defined as the percentage of embryos that successfully implant relative to the total number of embryos transferred. A transvaginal ultrasound will be performed during the fifth week of pregnancy to confirm implantation. The implantation rate will be calculated as the ratio of intrauterine gestational sacs to the total number of transferred embryos ( 11 ). Fetal growth up to the 12 th week: Fetal development will be monitored using transvaginal ultrasound up to the 12 th week of pregnancy to assess normal growth parameters. Ectopic pregnancy: The presence of an ectopic pregnancy, defined as implantation of embryo outside the uterine cavity (e.g., within the fallopian tube), will be evaluated through transvaginal ultrasound. Miscarriage: Miscarriage will be defined as the termination of pregnancy, either by expulsion of the fetus or by the absence of a detectable fetal heartbeat during ultrasound examination. Based on data regarding the endometrial thickness variable from the study by Shabiti et al. ( 15 ) and the sample size formula, assuming a significance level (α) of 0.05, a statistical power (1-β) of 80%, and a Type II error rate of 20%, the minimum required sample size for each group was estimated to be nine subjects. Accounting for a probable dropout rate of approximately 20%, a total of 22 volunteers (11 per group) will be recruited. Due to the limited number of previous studies in this field, the effect size was not calculated. Recruitment will begin with initial contact and consultation with potential volunteers. After confirmation eligibility, participants will receive detailed information about the study objectives and procedures. Those who agree to participate will provide written informed consent before enrollment. Demographic information, including age, height, weight, and body mass index (BMI), will be collected at this stage. After baseline data collection, 22 participants will be randomly assigned to one of two groups (n=11 per group) using a secure web-based randomization system to ensure unbiased allocation. This trial will compare the effects of pelvic physiotherapy combined with pharmacotherapy versus pharmacotherapy alone. The study protocol is illustrated in Figure 2. Study flow diagram of participant recruitment, allocation, intervention, and assessment. Randomization will be performed using block randomization with variable block sizes ( 3 , 6 , and 9). A secure web-based system will manage central randomization with an allocation ratio of 1:1. Block selection will continue until all 22 participants are assigned to one of two groups: the pharmacotherapy control group or the pelvic physiotherapy with pharmacotherapy intervention group. The random allocation sequence will be computer-generated by an independent researcher who is not involved in participant enrollment or assessment. Allocation concealment will be maintained by using opaque, sealed, sequentially numbered envelopes containing the intervention assignments. The envelopes will be opened by the gynecologist in the order of participant enrollment, and the corresponding intervention will then be prescribed. To minimize potential bias, participants will be instructed not to disclose their assigned group to the examiner or outcome assessors. The allocation sequence generation, participant enrollment, and assignment to study groups will be managed by a researcher who is not otherwise involved in the study to ensure impartiality and minimize selection bias. Due to the nature of the interventions, blinding of participants, the gynecologist, and the physiotherapist is not feasible. However, the primary outcome assessor (an expert sonographer) will remain blinded to group allocation. In addition, an independent examiner, also blinded to the intervention assignments, will collect demographic information, questionnaire responses, and pregnancy outcome data. Outcome assessors will remain blinded throughout the assessment process. However, unblinding may occur after all participant assessments are completed if necessary for data verification or safety reporting purposes. All interventions will be administered by a certified pelvic floor physiotherapist who is independent of the assessment process. A separate researcher, blinded to group al-location, will be responsible for monitoring and recording any adverse events during and after each treatment session. Data collection: Following embryo transfer, the remaining secondary outcomes will be assessed. The chemical pregnancy rate will be determined by measuring serum β-hCG levels. In cases of positive chemical pregnancy, clinical pregnancy, implantation rate, fetal growth up to the 12th week, miscarriage, and ectopic pregnancy will be monitored accordingly. First assessment: Following group allocation and prior to the start of interventions (tenth day of the menstrual cycle), transvaginal ultrasound will be performed to evaluate uterine blood supply status (arterial resistance index, pulsatility index, and S/D ratio), endometrial pattern, and endometrial thickness. Participants will complete the Persian versions of the FSFI, BDI, and SQOL-F questionnaires to assess sexual function, depression, and sexual quality of life, respectively. Assistance will be provided if required. Second assessment: After completion of the interventions in both groups and prior to embryo implantation (tenth day of the subsequent menstrual cycle), participants will be reassessed. Uterine blood supply, endometrial pattern, and endometrial thickness will be re-evaluated, and participants will again complete the FSFI, BDI, and SQOL-F questionnaires. Third assessment: In cases of successful implantation, chemical pregnancy will be determined by measuring serum β-hCG levels 14 days after cleavage-stage embryo transfer and 12 days after blastocyst-stage transfer. Two weeks following a positive chemical pregnancy test, transvaginal ultrasound will be performed to assess clinical pregnancy, the number of gestational sacs, and fetal heart rate. Data management: All participant information will be recorded on paper forms and subsequently entered into a secure computer database (Excel) according to a predefined numerical order. Statistical analysis: Data will be analyzed using SPSS version 25 (SPSS Inc., Chicago, IL, USA). Descriptive statistics will be calculated for demographic variables, including age, height, weight, BMI, the number of previous IVF cycles. The Kolmogorov-Smirnov test will be used to assess the normality of quantitative data. Depending on the data distribution, appropriate parametric or non-parametric tests will be applied. Within-group changes before and after the intervention will be compared using paired t-tests, while between-group differences will be assessed using one-way ANOVA. The Kruskal-Wallis test will be applied if data are not normally distributed or if variances are unequal. Categorical data will be analyzed using chisquare tests. Statistical significance will be set at P<0.05. Managing non-adherence and loss of follow-up: Intention-to-treat analysis will be performed to address nonadherence and missing data. Criteria for altering or stopping assigned treatments: Participants who choose to discontinue treatment or miss two consecutive sessions will be withdrawn from the study and replaced with another eligible participant. Strategies to enhance compliance with interventions: To promote adherence, all therapeutic interventions will be provided free of charge. Participants will have access to online or telephone support from their therapist to address any clinical questions. They will also be assured of their physical and mental safety, as well as the confidentiality of their personal information. Relevant concomitant care permitted or prohibited during the trial: Participants are instructed to refrain from traditional treatments throughout the study period. If any medication becomes necessary, participants must consult with the gynecologist to avoid potential drug interactions. Strategies to encourage participants adherence and program completion: During the intervention period, the gynecologist will monitor participants’ medication adherence. Participants will also be encouraged by the physiotherapist to attend physiotherapy sessions regularly. The physiotherapist will provide in-person or telephone support for questions regarding therapy exercises. All treatment procedures will be provided free of charge. Adverse events: A designated researcher will be responsible for reporting any adverse events related to pharmacotherapy, electrotherapy, pelvic floor exercises, and TECAR therapy. Monitoring of data collection: The trial will be overseen by members of the Physical Therapy Department at the Rehabilitation Faculty of Tabriz University of Medical Sciences. No interim analyses or audits are planned. Management of harms and post-intervention medical care: Participants will be informed of potential side effects associated with pharmacotherapy, electrotherapy, and TECAR therapy. Any adverse events will be managed by expert physiotherapists and gynecologists. The research team will address all complications and provide appropriate compensation for any resulting harm. Protocol amendments: Any amendments to the protocol will be submitted to the registry website to ensure transparency and compliance with ethical standards.