Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche: Protocol for a prospective, randomized, double-blinded, placebo-controlled clinical trial

Dazhi Fan, Shuzhen Wu, Shaoxin Ye, Wen Wang, Xiaoling Guo, Zhengping Liu, Dazhi Fan, Shuzhen Wu, Shaoxin Ye, Wen Wang, Xiaoling Guo, Zhengping Liu

Abstract

Background: Uterine niche is defined as a triangular anechoic structure at the site of the scar or a gap in the myometrium at the site of a previous caesarean section. The main clinical manifestations are postmenstrual spotting and intrauterine infection, which may seriously affect the daily life of nonpregnant women. Trials have shown an excellent safety and efficacy for the potential of mesenchymal stem cells (MSCs) as a therapeutic option for scar reconstruction. Therefore, this study is designed to investigate the safety and efficacy of using MSCs in the treatment for the uterine niche.

Methods/design: This phase II clinical trial is a single-center, prospective, randomized, double-blind, placebo-controlled with 2 arms. One hundred twenty primiparous participants will be randomly (1:1 ratio) assigned to receive direct intramuscular injection of MSCs (a dose of 1*10 cells in 1 mL of 0.9% saline) (MSCs group) or an identical-appearing 1 mL of 0.9% saline (placebo-controlled group) near the uterine incision. The primary outcome of this trial is to evaluate the proportion of participants at 6 months who is found uterine niche in the uterus by transvaginal utrasonography. Adverse events will be documented in a case report form. The study will be conducted at the Department of Obstetric of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan.

Discussion: This trial is the first investigation of the potential for therapeutic use of MSCs for the management of uterine niche after cesarean delivery.

Conclusion: This protocol will help to determine the efficacy and safety of MSCs treatment in uterine niche and bridge the gap with regards to the current preclinical and clinical evidence.

Trial registration number: NCT02968459 (Clinical Trials.gov: http://clinicaltrials.gov/).

Figures

Figure 1
Figure 1
Chart of trial design.
Figure 2
Figure 2
Direct intramuscular injection sites. (A) Real scene showing injection sites; (B) Schematic drawing showing injection sites. Injection sites will be selected near the incision at evenly 20 different sites.
Figure 3
Figure 3
Schematic drawing showing niche parameters. (A) Longitudinal section of the uterus; (B) transverse section of the uterus. D = depth of the triangular hypoechoic scar niche; L = length of the triangular hypoechoic scar niche; RMT = residual myometrial thickness; W = width of the triangular hypoechoic scar niche.

References

    1. Graham W, Woodd S, Byass P, et al. Diversity and divergence: the dynamic burden of poor maternal health. Lancet 2016;388:2164–75.
    1. Peleg D, Eberstark E, Warsof SL, et al. Early wound dressing removal after scheduled cesarean section: a randomized controlled trial. Am J Obstet Gynecol 2016;215:388.e1–5.
    1. Weinstein RA, Boyer KM. Antibiotic prophylaxis for cesarean delivery: when broader is better. N Engl J Med 2016;375:1284–6.
    1. Li HT, Luo S, Trasande L, et al. Geographic variations and temporal trends in cesarean delivery rates in China, 2008–2014. JAMA 2017;317:69–76.
    1. Lumbiganon P, Laopaiboon M, Gulmezoglu AM, et al. Method of delivery and pregnancy outcomes in Asia: the WHO global survey on maternal and perinatal health 2007–08. Lancet 2010;375:490–9.
    1. Liu S, Liston RM, Joseph KS, et al. Maternal mortality and severe morbidity associated with low-risk planned cesarean delivery versus planned vaginal delivery at term. CMAJ 2007;176:455–60.
    1. Silver RM. Delivery after previous cesarean: long-term maternal outcomes. Semin Perinatol 2010;34:258–66.
    1. Silver RM. Abnormal placentation: placenta previa, vasa previa, and placenta accreta. Obstet Gynecol 2015;126:654–68.
    1. Fan DZ, Wu S, Wang W, et al. Prevalence of placenta previa among deliveries in Mainland China: a PRISMA-compliant systematic review and meta-analysis. Medicine 2016;95:e5107.
    1. Bij de Vaate AJ, Brolmann HA, van der Voet LF, et al. Ultrasound evaluation of the Cesarean scar: relation between a niche and postmenstrual spotting. Ultrasound Obstet Gynecol 2011;37:93–9.
    1. Bij de Vaate AJ, van der Voet LF, Naji O, et al. Prevalence, potential risk factors for development and symptoms related to the presence of uterine niches following Cesarean section: systematic review. Ultrasound Obstet Gynecol 2014;43:372–82.
    1. Pomorski M, Fuchs T, Rosner-Tenerowicz A, et al. Standardized ultrasonographic approach for the assessment of risk factors of incomplete healing of the cesarean section scar in the uterus. Eur J Obstet Gynecol Reprod Biol 2016;205:141–5.
    1. Liu SJ, Lv W, Li W. Laparoscopic repair with hysteroscopy of cesarean scar diverticulum. J Obstet Gynaecol Res 2016;42:1719–23.
    1. Schepker N, Garcia-Rocha GJ, von Versen-Hoynck F, et al. Clinical diagnosis and therapy of uterine scar defects after caesarean section in non-pregnant women. Arch Gynecol Obstet 2015;291:1417–23.
    1. Fabres C, Arriagada P, Fernandez C, et al. Surgical treatment and follow-up of women with intermenstrual bleeding due to cesarean section scar defect. J Minim Invasive Gynecol 2005;12:25–8.
    1. Roberge S, Demers S, Berghella V, et al. Impact of single- vs double-layer closure on adverse outcomes and uterine scar defect: a systematic review and metaanalysis. Am J Obstet Gynecol 2014;211:453–60.
    1. Osser OV, Jokubkiene L, Valentin L. Cesarean section scar defects: agreement between transvaginal sonographic findings with and without saline contrast enhancement. Ultrasound Obstet Gynecol 2010;35:75–83.
    1. Tahara M, Shimizu T, Shimoura H. Preliminary report of treatment with oral contraceptive pills for intermenstrual vaginal bleeding secondary to a cesarean section scar. Fertil Steril 2006;86:477–9.
    1. Raimondo G, Grifone G, Raimondo D, et al. Hysteroscopic treatment of symptomatic cesarean-induced isthmocele: a prospective study. J Minim Invasive Gynecol 2015;22:297–301.
    1. Lin YH, Hwang JL, Seow KM. Endometrial ablation as a treatment for postmenstrual bleeding due to cesarean scar defect. Int J Gynaecol Obstet 2010;111:88–9.
    1. Li C, Guo Y, Liu Y, et al. Hysteroscopic and laparoscopic management of uterine defects on previous cesarean delivery scars. J Perinat Med 2014;42:363–70.
    1. Zhou J, Yao M, Wang H, et al. Vaginal repair of cesarean section scar diverticula that resulted in improved postoperative menstruation. J Minim Invasive Gynecol 2016;23:969–78.
    1. Luo L, Niu G, Wang Q, et al. Vaginal repair of cesarean section scar diverticula. J Minim Invasive Gynecol 2012;19:454–8.
    1. Pajoohesh M, Naderi-Manesh H, Soleimani M. MicroRNA-145-based differentiation of human mesenchymal stem cells to smooth muscle cells. Biotechnol Lett 2016;38:1975–81.
    1. Jin M, Wu Y, Wang Y, et al. MicroRNA-29a promotes smooth muscle cell differentiation from stem cells by targeting YY1. Stem Cell Res 2016;17:277–84.
    1. Jafarian A, Taghikani M, Abroun S, et al. The generation of insulin producing cells from human mesenchymal stem cells by MiR-375 and anti-MiR-9. PLoS One 2015;10:e0128650.
    1. Chen H, Yang H, Yue H, et al. Mesenchymal stem cells expressing eNOS and a Cav1 mutant inhibit vascular smooth muscle cell proliferation in a rat model of pulmonary hypertension. Heart Lung Circ 2017;26:509–18.
    1. Grieve SM, Bhindi R, Seow J, et al. Microvascular obstruction by intracoronary delivery of mesenchymal stem cells and quantification of resulting myocardial infarction by cardiac magnetic resonance. Circ Heart Fail 2010;3:e5–6.
    1. Schneider F, Saucy F, de Blic R, et al. Bone marrow mesenchymal stem cells stabilize already-formed aortic aneurysms more efficiently than vascular smooth muscle cells in a rat model. Eur J Vasc Endovasc Surg 2013;45:666–72.
    1. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895–904.
    1. Zhang S, Sun A, Xu D, et al. Impact of timing on efficacy and safety of intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction: a pooled subgroup analysis of randomized controlled trials. Clin Cardiol 2009;32:458–66.
    1. Dill T, Schachinger V, Rolf A, et al. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J 2009;157:541–7.
    1. Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586.
    1. Committee on Obstetric Practice. Committee opinion no. 688: management of suboptimally dated pregnancies. Obstet Gynecol 2017;129:e29–32.
    1. Monteagudo A, Carreno C, Timor-Tritsch IE. Saline infusion sonohysterography in nonpregnant women with previous cesarean delivery: the “niche” in the scar. J Ultrasound Med 2001;20:1105–15.
    1. Ji M, Bai C, Li L, et al. Biological characterization of sheep kidney-derived mesenchymal stem cells. Exp Ther Med 2016;12:3963–71.
    1. Kalladka D, Sinden J, Pollock K, et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 2016;388:787–96.
    1. Panes J, Garcia-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet 2016;388:1281–90.
    1. Guijarro D, Lebrin M, Lairez O, et al. Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: results of the MESAMI 1 pilot trial. Int J Cardiol 2016;209:258–65.
    1. Zhou SB, Zhang GY, Xie Y, et al. Autologous stem cell transplantation promotes mechanical stretch induced skin regeneration: a randomized phase I/II clinical trial. EBioMedicine 2016;13:356–64.

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