Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial

J F W Rikken, C R Kowalik, M H Emanuel, M Y Bongers, T Spinder, F W Jansen, A G M G J Mulders, R Padmehr, T J Clark, H A van Vliet, M D Stephenson, F van der Veen, B W J Mol, M van Wely, M Goddijn, J F W Rikken, C R Kowalik, M H Emanuel, M Y Bongers, T Spinder, F W Jansen, A G M G J Mulders, R Padmehr, T J Clark, H A van Vliet, M D Stephenson, F van der Veen, B W J Mol, M van Wely, M Goddijn

Abstract

Study question: Does septum resection improve reproductive outcomes in women with a septate uterus?

Summary answer: Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus.

What is known already: A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant.

Study design, size, duration: We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018.

Participants/materials, setting, methods: Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI.

Main results and the role of chance: We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%).

Limitations, reasons for caution: Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance.

Wider implications of the findings: The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery.

Study funding/competing interest(s): There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare.

Trial registration number: Dutch trial registry: NTR 1676.

Trial registration date: 18 February 2009.

Date of first patient’s enrolment: 20 October 2010.

Keywords: live birth; pregnancy loss; septate uterus; septum resection; subfertility.

© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.

Figures

Figure 1.
Figure 1.
Trial profile. *One woman withdrew informed consent immediately after being randomized as she did not prefer a septum resection. **Two women appeared to have no septate uterus at time of surgery and hence septum resection was cancelled. ***One woman had a septum resection after 1 month, three women after 4 months and one woman after 9 months of follow-up.
Figure 2.
Figure 2.
Kaplan–Meier analysis of cumulative live birth rate in women who underwent septum resection and women who had expectant management.

References

    1. AFS. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944–955.
    1. ASRM. Uterine septum: a guideline. Fertil Steril 2016;106:530–540.
    1. Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J; the Born Too Soon Preterm Birth Action Group (see acknowledgement for full list). Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013;10:S2.
    1. Braakhekke M, Kamphuis EI, Dancet EA, Mol F, van der Veen F, Mol BW.. Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper. Fertil Steril 2014;101:1203–1204.
    1. Chan YY, Jayaprakasan K, Tan A, Thornton JG, Coomarasamy A, Raine-Fenning NJ.. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound Obstet Gynecol 2011a;38:371–382.
    1. Chan YY, Jayaprakasan K, Zamora J, Thornton JG, Raine-Fenning N, Coomarasamy A.. The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review. Hum Reprod Update 2011b;17:761–771.
    1. ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B, Quenby S, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; doi: 10.1093/hropen/hoy004. PMID: 31486805; PMCID: PMC6276652.
    1. Faivre E, Fernandez H, Deffieux X, Gervaise A, Frydman R, Levaillant JM.. Accuracy of three-dimensional ultrasonography in differential diagnosis of septate and bicornuate uterus compared with office hysteroscopy and pelvic magnetic resonance imaging. J Minim Invasive Gynecol 2012;19:101–106.
    1. Graupera B, Pascual MA, Hereter L, Browne JL, Ubeda B, Rodriguez I, Pedrero C.. Accuracy of three-dimensional ultrasound compared with magnetic resonance imaging in diagnosis of Mullerian duct anomalies using ESHRE-ESGE consensus on the classification of congenital anomalies of the female genital tract. Ultrasound Obstet Gynecol 2015;46:616–622.
    1. Grimbizis GF, Gordts S, Di Spiezio Sardo A, Brucker S, De Angelis C, Gergolet M, Li TC, Tanos V, Brolmann H, Gianaroli L. et al. The ESHRE-ESGE consensus on the classification of female genital tract congenital anomalies. Gynecol Surg 2013;10:199–212.
    1. Homer HA, Li TC, Cooke ID.. The septate uterus: a review of management and reproductive outcome. Fertil Steril 2000;73:1–14.
    1. Ludwin A, Martins WP, Nastri CO, Ludwin I, Coelho Neto MA, Leitao VM, Acien M, Alcazar JL, Benacerraf B, Condous G. et al. Congenital Uterine Malformation by Experts (CUME): better criteria for distinguishing between normal/arcuate and septate uterus? Ultrasound Obstet Gynecol 2018;51:101–109.
    1. Ludwin A, Pityński K, Ludwin I, Banas T, Knafel A.. Two- and three-dimensional ultrasonography and sonohysterography versus hysteroscopy with laparoscopy in the differential diagnosis of septate, bicornuate, and arcuate uteri. J Minim Invasive Gynecol 2013;20:90–99.
    1. NICE. Guideline: Hysteroscopic metroplasty of a uterine septum for primary infertility. 2015:1–8.
    1. RCOG. Guideline: The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. 2011:1–18.
    1. Rikken JFW, Kowalik CR, Emanuel MH, Bongers MY, Spinder T, de Kruif JH, Bloemenkamp KWM, Jansen FW, Veersema S, Mulders AGMGJ. et al. The randomised uterine septum transsection trial (TRUST): design and protocol. BMC Women's Health 2018;18:163.
    1. Rikken JFW, Verhorstert KWJ, Emanuel MH, Bongers MY, Spinder T, Kuchenbecker W, Jansen FW, van der Steeg JW, Janssen CAH, Kapiteijn K. et al. Septum resection in women with a septate uterus: a cohort study. Hum Reprod 2020;35:1722–1722.
    1. Saravelos SH, Cocksedge KA, Li TC.. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum Reprod Update 2008;14:415–429.
    1. Siam S, Soliman BS.. Combined laparoscopy and hysteroscopy for the detection of female genital system anomalies results of 3,811 infertile women. J Reprod Med 2014;59:542–546.
    1. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID. et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 2017;32:1786–1801.
    1. Zhang Y, Yang L, Yang SL, Zhao Q, Xie Y.. Ultrasonography versus laparoscopy in transcervical resection of septa: a randomized clinical trial. Clin Exp Obstet Gynecol 2015;42:515–517.

Source: PubMed

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