A combination protocol of vitamin D, prednisone, aspirin, and vitamin B-folate complex improves ongoing pregnancy rates in pateints with recurrent pregnancy loss or multiple failed euploid single embryo transfer cycles
While preimplantation genetic testing (PGT) is increasingly being utilized to identify euploid embryos and to improve the likelihood of successful outcomes, many patients still experience recurrent pregnancy loss (RPL) and/or repeated implantation failure (RIF). Patients who experience RPL and/or RIF must cope with physical and emotional distress. Reproductive immunologists often utilize combination medication therapies to treat patients with RPL and RIF, however, these protocols often are not well supported by evidence-based research. This study evaluated the clinical outcomes for RIF and RPL patients who were treated with a specific combination protocol.
Design
Retrospective, cohort study.
Materials and Methods
The study included patients who underwent single, euploid frozen embryo transfers (FET) with the combination medication therapy from 2014 - 2018. The combination medication protocol includes: Vitamin D, Prednisone, Aspirin and a Vitamin-B12/Vitamin B6/ Folate (CBF) complex. Patients with a history of R 2 failed euploid, single embryo transfers (SET), R 3 clinical spontaneous abortions (SAB), or a combination of 2 SABs and 1 failed SET were included in the analysis. Only patients who utilized autologous oocytes were included.
Results
A total of 54 IVF-FET cycles meeting criteria were included. Patient average age was 35.74 years old (range: 24 - 44). Upon review of the cycle outcomes, a total of 79.62% (n=43/54) achieved positive clinical pregnancy rates. Of those who attained a positive clinical pregnancy, 72.09% (n=31/43) reached at least 8 weeks gestation. Of those who passed the 8week gestation period, 74.19% (23/31) reached their estimated date of delivery and 91.30% of those (n=21/23) achieved live birth. A total of 14.81% (n=8/54) cycles resulted in clinical pregnancy loss and 7.41% (n=4/54) resulted in biochemical pregnancy loss. Finally, 20.38% (n=11/54) cycles resulted in negative pregnancy tests.
Conclusions
While the etiology of RPL and RIF are not well understood, our study sought to identify an affordable and minimally invasive alternative treatment regimen. Due to the high levels of anxiety and distress associated with failed euploid embryo transfer cycles and spontaneous abortions, we sought to develop a new viable treatment strategy. Although the study was limited by sample size and design, the results were encouraging and future randomized control trials should be done to provide further support for this combination-medication treatment protocol.
Kuroda K et al., 2021·Reprod Med Biol·
Open Access
Does the OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy, developed for treating repeated implantation failure (RIF), contribute to improving pregnancy outcomes in patients with a history of recurrent pregnancy loss (RPL)? Between 2018 and 2019, women with RPL after two or more clinical pregnancy losses underwent RPL testing. We treated chronic endometritis with antibiotics, high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of 168 consecutive women aged ≤43 years, 115 underwent RPL testing. We compared 100 pregnancies (90 women) and 46 pregnancies (41 women) with and without the OPTIMUM treatment strategy, respectively. RPL testing identified intrauterine abnormalities in 66 (57.4%), elevated Th1/Th2 cell ratios in 50 (43.5%), thyroid dysfunction in 33 (28.7%), and thrombophilia in 33 (28.7%). The live birth rate in the OPTIMUM group was significantly higher than that in the control group among women aged <40 years (78.1% and 42.3%, respectively; p = 0.002), but no significant difference was observed in women aged ≥40 years (55.6% and 30.0%, respectively; p = 0.09). The OPTIMUM treatment strategy improved pregnancy outcomes in patients with not only RIF but also RPL.
Almohammadi A et al., 2025·International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
[BACKGROUND] Recurrent implantation failure (RIF) has a multifactorial etiology. An umbrella review was undertaken to evaluate the multiple proposed interventions. [OBJECTIVES] To summarize and assess the strength of evidence of interventions for RIF from published systematic reviews (SR) of randomized clinical trials (RCTs). [SEARCH STRATEGY] After prospective registration (PROSPERO CRD42023414255), a systematic search was conducted in the Cochrane Library, Scopus and Medline from inception until March 2024. [SELECTION CRITERIA] SRs of RCTs, with or without meta-analyses (MA), were included if they reported clinical pregnancy rates (CPR) or live birth rates (LBR). [DATA COLLECTION AND ANALYSIS] The methodological quality of the included SRs was appraised independently in duplicate using the AMSTAR 2 tool. For each intervention, the MAs of RCTs with statistically significant improvements were counted as a percentage of the total assessing the strength of evidence using the GRADE system. [MAIN RESULTS] A total of 47 SRs were included: 32 reviews covered immunomodulatory interventions, 10 (68 RCTs) covered uterine and endometrial interventions, one covered antibiotics, and four (69 RCTs) addressed mixed approaches, including laboratory interventions. AMSTAR 2 appraised 41 (88%) SRs as critically low or low, and 6 (12%) as moderate or high in quality. The SRs often had a level of overlap of RCTs (median 33.3%), inconsistent definitions of RIF, and varied comparisons for the interventions. Considering the significant meta-analytic evidence of high-moderate GRADE strength: Granulocyte colony-stimulating factor (G-CSF) showed improvement in CPR in 9/13 (69.2%) MAs and LBR in 1/7 (14%); intralipid infusion showed improvement in CPR in 4/6 (57.14%) MAs and LBR in 3/4 (75%); peripheral blood mononuclear cells (PBMC) showed improvement in CPR in 4/8 (50%) MAs and LBR 3/5 (60%); platelet-rich plasma (PRP) intervention showed improvement in CPR in 6/10 (60%) MAs and LBR in 1/5 (20%); human chorionic gonadotropins showed improvement in CPR in 3/3 (100%) MAs; growth hormone showed improvement in CPR in 1/1 (100%) MA; low molecular weight heparin showed improvement in CPR in 1/1 (100%) MAs and LBR in 1/2 (50%); hysteroscopy showed improvement in CPR in 1/2 (50%) MAs; and, intentional endometrial injury showed improvement in CPR in 3/4 (75%) MAs and LBR in 2/3 (66.66%). [CONCLUSIONS] Evidence syntheses of RCTs evaluating interventions for RIF suggest a consistent direction, with high to moderate strength, indicating that immunomodulatory treatments, including G-CSF, PBMC, PRP, intralipid infusion, and intentional endometrial injury are likely to be effective. However, this conclusion should be interpreted with caution due to the generally low methodological quality of the included studies and the clinical heterogeneity observed in most SRs.
[OBJECTIVE] The role of intrauterine PRP infusion in managing recurrent implantation failure (RIF) remains controversial despite its emerging clinical use. This systematic review aims to evaluate its therapeutic potential in RIF patients and further to investigate variations in outcomes based on transfer cycle type, embryo developmental stage, RIF diagnostic criteria, and endometrial thickness. [METHODS] We systematically searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Scopus, and Web of Science for randomized controlled trials (RCTs) investigating PRP treatment for RIF patients from the beginning of the database to May 2025. [RESULTS] This meta-analysis showed that PRP administration significantly improved clinical pregnancy rate (CPR) [OR = 3.18, 95%CI (2.45, 4.14), I2 = 3%], biochemical pregnancy rate (BPR) [OR = 2.84, 95%CI (2.22, 3.63), I2 = 0%], ongoing pregnancy rate (OPR) [OR = 3.41, 95%CI (2.08, 5.60), I2 = 30%] and live birth rate (LBR) [OR=5.10, 95%CI (1.95, 13.37), I2 = 75%] in women with RIF. However, PRP intrauterine infusion did not reduce miscarriage rate (MR). Notably, the preterm birth rate was significantly higher in the PRP group compared to controls [OR = 8.24, 95%CI (2.09, 32.41), I2 = 0%]. Subgroup analysis demonstrated that PRP improved CPR, BPR and LBR in both the fresh and frozen embryo transfer cycles. Additionally, while PRP increased CPR, LBR and reduced MR in blastocyst transfers [CPR OR = 3.84, 95%CI (2.82, 5.23), I2 = 0%; LBR OR = 7.32, 95%CI (3.17, 16.90), I2 = 63%; MR OR = 0.27, 95%CI (0.07, 0.96), I2 = 54%], these effects were not observed in cleavage-stage embryo transfers. Moreover, PRP administration associated with a higher CPR [OR = 3.84, 95%CI (2.82, 5.23), I2 = 0%], OPR[OR = 4.13, 95%CI (1.79, 9.56), I2 = 48%], LBR [OR = 7.32, 95%CI (3.17, 16.90), I2 = 63%] and a lower MR [OR = 0.27, 95%CI (0.07, 0.96), I2 = 54%] in women with ≥3 prior implantation failure, it did not confer the same benefit to those with a history of ≥2 failed cycles. [CONCLUSION] These findings suggest a possible beneficial role for PRP on pregnancy outcomes to some extent in women with RIF, particularly in cases with ≥3 prior failed transfers, and blastocyst transfer may increase LBR and reduce miscarriage risk. However, further investigation is warranted to determine whether this treatment may pose an increased risk of preterm birth. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/prospero/, identifier CRD420251061511.
Outcomes and Effectiveness · Outcomes by Diagnosis
Li J et al., 2023·Frontiers in cell and developmental biology
Chronic endometritis (CE) has been considered to reduce uterine receptivity and negatively affect reproductive outcomes for in vitro fertilization-embryo transfer (IVF-ET) patients, especially for people undergoing recurrent implantation failure (RIF). To investigate the effects of antibiotic and platelet-rich plasma (PRP) therapy on pregnancy outcomes following frozen-thawed embryo transfer (FET) in RIF patients with CE, endometrial specimens of 327 patients with RIF obtained by endometrial scratching during mid-luteal phase were immunostained by multiple myeloma oncogene-1 (Mum-1)/syndecan-1 (CD138). RIF patients with CE were given antibiotics and PRP treatment. According to the Mum-1+/CD138+ plasmacytes after treatment, patients were divided into persistent weak positive CE (+) group, CE (-) group and non-CE group. FET was performed and the basic characteristics and pregnancy outcomes of patients in three groups were compared. Among 327 RIF patients, 117 patients were complicated with CE, the prevalence was 35.78%. The prevalence of strong positive was 27.22% and that of weak positive was 8.56%. 70.94% patients with CE converted to negative after treatment. There was no significant difference in the basic characteristics, including age, BMI, AMH, AFC, infertility years, infertility types, number of previous transplant cycles, endometrial thickness on transplantation day and number of transplanted embryos (p > 0.05); The positive rate of hCG, clinical pregnancy rate and implantation rate in CE (-) group were significantly increased compared with the weak CE (+) group and non-CE group (p < .01), and the live birth rate also improved (p < .05). Whereas, the rate of early abortion in CE (-) group was 12.70%, which was higher than that in weak CE (+) group and non-CE group (p < .05). After multivariate analysis, number of previous failed cycles and CE remained independent factors associated with live birth rate, while only CE remained to be the independent factor of clinical pregnancy rate. It is recommended to perform CE-related examination for patients with RIF. Antibiotic and PRP treatment can significantly improve pregnancy outcomes of patients with CE negative conversion in FET cycle.