Reviewer ’s report  
 
Title: The randomised uterine septum transsecti on trial (TRUST): Design and protocol  
 
Version: 3 Date: 14 Aug 2017  
 
Reviewer: Ludwin Artur  
 
Reviewer's report:  
SUMMARY OF CONTENT  
 
Manuscript contains the recent form of protocol of multicenter randomized controlled trial: the 
randomized uterine septum transs ection trial (TRUST); NTR 1676; 
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1676 .  
Online information: http://www.studies -obsgyn.nl/trust/page.asp?page_id=674   
 
OVERALL OPINION  
 
The randomized controlled trial is important, because hysterosco pic metroplasty in women with 
septate uterus and miscarriages or infertility is performed without robust evidence. However 
publication of the recent protocol without the first form of protocol is not the best way for 
understanding potential limitations of the trial. Readers may underestimate the weaknesses of the 
study, and importance of final report may be overrated. Therefore, the manuscript should contain 
these important details.  
 
The protocol, primary hypothesis, primary target population, and diagnost ic criteria for 
recognition of septate uterus were significantly changed in final stage of the study (2014, 2016). 
National Dutch study was changed to international study. Therefore, it is important to include all 
information about the changes, and elucida te reasons and rationale for these changes.  Authors 
should discuss the potential impact of these changes on the results. The sample size was 
calculated based on data from women with recurrent miscarriages, but finally, the study included 
women after one m iscarriage or subfertility and after preterm birth. The proportion of sample by 
specific changes in the protocol regarding the changes of inclusion criteria (different definition 
of septate uterus) should be shown.  
 
Nowadays, we better understand the problem of used diagnostic tools, as well as limitations of 
diagnostic criteria for septate uterus.  
 
The main problem of the study protocol is a definition of septate uterus (see below), and it 
should be widely discussed  in the manuscript:  
 
- The criteria for recognition of septate uterus used in the first stage of the study (5 years) 
were significantly different from these used after 2014, as well as 2016. It may be the most 
important problem for validity of this study b ecause in the first period women with septate uterus 
with length of ¼ of uterine cavity were included, in second period women with suspicion of 
septate uterus were included, and in the final phase of the study women with septate uterus 
without clear/reliab le definition (lack of morphometric criteria) were included.  
- The used diagnostic tools with described methodology for recognition of septate uterus 
are unreliable or their inter -observer reliability is unknown;  
- Therefore part of women with normal, arc uate uterus can be the participants of TRUST; 
It is difficult to assess how many women with normal or normal/arcuate uterus in comparison to 
available strict definitions was included in the trial.  
- It should be highlighted that the study cannot generalize  the study result relative to the 
new diagnostic criteria officially endorsed by ASRM (Salim et al., 2003; Ludwin et al., 2011; 
ASRM 2016), and especially for the definition of septate uterus by ESHRE -ESGE, which reflect 
70% of normal and arcuate uterus by  ASRM (Ludwin et al., 2015).  
 
GENERAL COMMENTS  
 
The manuscript should include all changes and their rationale in study protocol (hypotheses, 
inclusion criteria, definitions). For instance the changes of inclusion criteria may reflect the low 
rate of inclu ded women with recurrent miscarriages (it has been reported in Dutch meetings that 
women with recurrent miscarriages didn't want to be a subject of randomization).  
 
I suggest describing the first form of protocol with changes step by step. It will reflect  real 
problems of the study. Background, methods and discussion should be improved accordingly.  
 
Other important points:  
 
1. Ethical consideration (Hazardous trial) should be widely discussed. RCT in women with 
recurrent miscarriages was considered as unet hical and redundant by other authors (i.e. Valle et 
al., 2013), and still is controversial, because there are many data from non -randomized studies. 
Did the written consent include information of these results or about lack of evidence suggesting 
preferenc e for hysteroscopic metroplasty?  
 
2. Definition of septate uterus: I suggest using of separate subheading about definition of 
septate uterus:  
 
- changes of definition during the study period should be explained  
- weaknesses (unknown reliability, and prob ably unreliable definition of septate uterus) of 
used definitions should be discussed including available evidence about accuracy and reliability 
of diagnostic tools and criteria  
- lack of validity and generalizability of the results relative to current mo rphometric criteria 
for septate uterus should be emphasized and discussed.  
- high risk of inclusion patients with normal uterus and arcuate uterus by used definition 
should be discussed;  
- lack of validation of used definition between centers/observers sh ould be discussed  
- The study without strict definition (for instance the reliability of hysteroscopy may be 
very low; 0.2 or 0.5: Smith et al. 2013, 2016; but in reality the reliability of hysteroscopy is 
unknown (Ludwin and Ludwin 2016). Moreover, reliab ility of 3D US without any criteria may 
be questionable, because only reliability of 3D US with specific criteria was tested (Salim et al., 
2003; Ludwin et al., 2015), the inter -rater/intra -rater reliability of used tools is unknown).  
 
 
3. Diagnostic tools (I suggest using separate subheading)  
- rationale for their use  
- limitation regarding accuracy and inter -rater reliability  
 
4. Inclusion criteria  
- please confirm that women without miscarriage, subfertility and preterm births were no t 
considered as candidate for the trial  
 
5. Hysteroscopic metroplasty  
- adhesion prophylaxis: yes or no?  
- manner of ultrasound guidance: transabdominal, transrectal, 2D or 3D ?  
- please explain your intraoperative criteria for complete septum resection i n context of 
other used criteria in ultrasound (Ludwin et al. 2014), and endoscopy; resection may be 
incomplete  
 
 
6. Second look hysteroscopy  
- Methodology  
- Rationale  
- Evaluation/classification of anatomical results - please explain your criteria in co ntext to 
other used criteria (residual septum 1cm; Fedele et al., 1996; residual septum + adhesions: 
Ludwin et al., 2014)  
- Secondary surgical procedures: allowed or not? Indication to potential intervention 
(adhesiolysis, resection of residual septum)  
 
 
7. Changes in the protocol  
 
I suggest summarizing all changes in protocol including relevant dates, and number (proportion 
of sample) of included patients before specific changes.  
 
 
Other subjects for description or clarification  
 
 1.  One of the exclusion criteria was: ‚prior randomization in the TRUST' - Is this criterion not 
used during the study?  
 
 
 
 
SPECIFIC COMMENT  
 
Abstract:  
 
The changes of protocol were significant and should be included.  
 
Line 64 Were these results in women with recurrent abortion (aim from 2008)?  
Is it possible to generalize these result and sample size calculation for three different population 
recently included: i) subfertile; ii) after one miscarriage; iii) with preter m birth?  
 
Background:  
 
The background should explain changes in hypothesis and aim, as well as rationale for these 
changes.  
 
Line 76 -79 Association between fertility and septate uterus is unclear and debatable. Other meta -
analysis showed lack of associati on between infertility and septate uterus, because there were not 
significant differences between prevalence in women with infertility, and women from general 
population (Chan et al., 2011; Human Reprod).  
 
Line 88 -90 I suggest showing the lowest and the h ighest estimations of prevalence from these 
meta -analyses.  
 
 
Line 113 -114 The study population was significantly different during the study.    
 
Line 121 This reference in this place is irrelevant, because the ESHRE -ESGE definition of 
septate uterus is: in ternal indentation > 50% of uterine wall thickness, and external cleft < 50% 
of uterine wall thickness. Author should confirm that they not use the ESHRE -ESGE definition 
in this study. If the definition of ESHRE -ESGE were used, it may destroy the study bec ause this 
definition is not well thought out and it is simply illogical: see the paradox of use the index based 
on uterine wall (the ESHRE -ESGE paradox: the use a variable and independent parameter from 
cavity deformity degree) (Ludwin and Ludwin, 2015).  
 
Discussion:  
 
Changes in the protocol and potential limitation associated with changes, as well as used 
definition of septate uterus should be discussed regarding possibility of generalization of the 
study results.  
The validity of this study may be limited  due to i) unreliable definition of septate uterus (lack of 
clear criteria for differentiation between septate, arcuate and normal uterus in the study), and ii) 
use of inaccurate diagnostic methods  in first period of study (HSG), and iii) changes in targe t 
study population.  
Significant part of study were performed using criteria, which meet the current definition of 
normal/arcuate uterus by ASRM (1/4 uterine cavity is < 1.5 cm of uterine cavity), same experts 
from ESGE (ie. 1/3 of uterine cavity), and other authors (Salim  et  al., 2003; Ludwin et al., 
2013).  
 
Lines 201 -203.  This statement is debatable: there is not a wide consensus about performing 
hysteroscopic metroplasty in women without reproductive failures (prophylactic metroplasty) 
(Valle and Ekpo, 2013; NICE 2013).  
  
 
Figure 1 I suggest showing in flow diagram the changes in inclusion criteria; In women after 
hysteroscopy was performed second look hysteroscopy, it should be explain in flow diagram. It 
is unclear what had happened during second look hysteroscopy (only  diagnostic hysteroscopy or 
intervention if residual septum or adhesions were present?)  
 
 
References  
 
1. Salim R, Woelfer B, Backos M, Regan L, Jurkovic D. Reproducibility of three -
dimensional ultrasound diagnosis of congenital uterine anomalies. Ultrasoun d Obstet Gynecol 
2003; 21: 578 -582. 
2. Ludwin A, Ludwin I, Banas T, Knafel A, Miedzyblocki M, Basta A. Diagnostic accuracy 
of sonohysterography, hysterosalpingography and diagnostic hysteroscopy in diagnosis of 
arcuate, septate and bicornuate uterus. J Obs tet Gynaecol Res 2011; 37: 178 -186. 
3. Ludwin A, Ludwin I. Comparison of the ESHRE -ESGE and ASRM classifications of 
Müllerian duct anomalies in everyday practice. Hum Reprod. 2015 Mar;30(3):569 -80. doi: 
10.1093/humrep/deu344.  
4. Uterine septum: a guideline . Practice Committee of the American Society for 
Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the 
American Society for Reproductive Medicine. Fertil Steril. 2016 Sep 1;106(3):530 -40. doi: 
10.1016/j.fertnstert.2016.05.014.  
5. Valle RF, Ekpo GE. Hysteroscopic metroplasty for the septate uterus: review and meta -
analysis. J Minim Invasive Gynecol 2013; 20: 22 -42. 
6. Smit JG, Kasius JC, Eijkemans MJ, Veersema S, Fatemi HM, Santbrink van EJ, Campo 
R, Broekmans FJ. The internatio nal agreement study on the diagnosis of the septate uterus at 
office hysteroscopy in infertile patients. Fertil Steril 2013; 99: 2108 -2113 e2102.  
7. Smit JG, Overdijkink S, Mol BW, Kasius JC, Torrance HL, Eijkemans MJ, Bongers M, 
Emanuel MH, Vleugels M, Br oekmans FJ. The impact of diagnostic criteria on the 
reproducibility of the hysteroscopic diagnosis of the septate uterus: a randomized controlled trial. 
Hum Reprod 2015; 30: 1323 -1330.  
8. Ludwin A, Ludwin I. Reliability of hysteroscopy -based diagnosis of septate, arcuate and 
normal uterus: estimate or guestimate? Hum Reprod 2016; 31: 1376 -1377.  
9. Smit JG, Torrance HL, Eijkemans MJ, Broekmans FJ. Reply: Reliability of 
hysteroscopy -based diagnosis of septate, arcuate and normal uterus: estimate or guestimat e? 
Hum Reprod 2016; 31: 1377 -1378.  
10. Ludwin A, Ludwin I, Kudla M, Kottner J. Reliability of the European Society of Human 
Reproduction and Embryology/European Society for Gynaecological Endoscopy and American 
Society for Reproductive Medicine classificat ion systems for congenital uterine anomalies 
detected using three -dimensional ultrasonography. Fertil Steril 2015; 104: 688 -697 e688.  
11. Ludwin A, Ludwin I, Pitynski K, Banas T, Jach R. Role of morphologic characteristics of 
the uterine septum in the pred iction and prevention of abnormal healing outcomes after 
hysteroscopic metroplasty. Hum Reprod 2014; 29: 1420 -1431.  
12. Ludwin A, Ludwin I, Kudla M, Pitynski K, Banas T, Jach R, Knafel A. Diagnostic 
accuracy of three -dimensional sonohysterography compared with office hysteroscopy and its 
interrater/intrarater agreement in uterine cavity assessment after hysteroscopic metroplasty. Fertil 
Steril. 2014 May;101:1392 -9. 
13. Chan YY, Jayaprakasan K, Zamora J, Thornton JG, Raine -Fenning N, Coomarasamy 
A.The preval ence of congenital uterine anomalies in unselected and high -risk populations: a 
systematic review. Hum Reprod Update. 2011 Nov -Dec;17(6):761 -71. doi: 
10.1093/humupd/dmr028.  
14. Grimbizis GF, Gordts S, Di Spiezio Sardo A, Brucker S, De Angelis C, Gergolet M , Li 
TC, Tanos V, Brolmann H, Gianaroli L, Campo R. The ESHRE/ESGE consensus on the 
classification of female genital tract congenital anomalies. Hum Reprod 2013; 28: 2032 -2044.  
15. Ludwin A, Pitynski K, Ludwin I, Banas T, Knafel A. Two - and three -dimension al 
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. 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
No 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
Yes 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an addition al statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
Not relevant to this manuscript  
Quality  of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
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