Reviewer ’s report  
 
Title: The randomised uterine septum transsection trial (TRUST): Design and protocol  
 
Version: 4 Date: 19 Dec 2017  
 
Reviewer: Ludwin Artur  
 
Reviewer's report:  
Although most of my points raised have been addressed accordingly, the paper still needs some 
important corr ections and clarifications getting more transparency of  the previous versions of 
protocol.  
 
SUMMARY  
 
All versions of this protocol, as published in the registries, should be followed and deviations 
explained and substantiated in the manuscript.  
The chan ges in the study population and varing definitions of septate uterus (some allow the 
inclusion of patients with normal and arcuate uterus) greatly increase the risk of false findings 
and should be more transparent.  
Retrospective re -classification by anoth er highly problematic and arbitrary definition (the 
ESHRE -ESGE, which reflect normal, arcuate and infrequently septate uterus in a recent 
validation study completed by 15 experts from 9 societies: the CUME: Ludwin et al., Ultrasound 
Obstet Gynecol 2017) ag gravate the risk of false interpretation and implication.  
Currently we have two conflicting definitions suggested by highly influencial societies in the 
field. Neither the reporting nor the interpretation should be biased towards any society 
(CONUTA/ESHRE -ESGE vs ASRM) if the definition was not used for consecutive inclusions, 
as in the trial.  
Because the recent validation study (CUME) shows good agreement amongst international 
experts while using the coronal view of the uterus to differentiate septate fr om a normal/arcuate 
uterus, and poor agreement with ESHRE -ESGE and ASRM criteria, which over - and 
underestimate, respectively, the prevalence of septate uterus, I strongly suggest registering the 
study protocol of the CUME definition for validating the mor fology of uteri, thus avoiding 
iatrogenic intervention on normal/arcuate uterus in the final period of the study.  
 
OVERALL OPINION  
 
My concerns are still focused on five crucial points:  
 
(I) The updated hypothesis;  
 
Despite of the authors' explanation, t he hypothesis may be considered as updated.  
Suggestion: the original and updated hypothesis should be described in the background 
according to the study register:  
 
The original hypothesis: ‚metroplasty in women with recurrent miscarriage and a septate ute rus 
will improve their reproductive outcome.' 
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1676 .' 
 
The updated hypothesis: ‚Metroplasty in women with recurrent miscarriage or subfertility and a 
septate uterus will improve reproductive outcome. ' 
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1676 . 
 
Factual status: Metroplasty in women with history of (recurrent) miscarriage/s or subfertility or 
preterm births and a septate uterus will improve reproductive outcome.  
 
The authors stated in the response:  
'our primary population consists of women of reproductive age with a septate uterus';  
 
It is a debatable statement in context to the register and supporting the systematic review 
(Kowalik et al., 2011) of the original hy pothesis. For such a described population the inclusion 
criteria are too restrictive; a study with the hypothesis targeting septate uterus should include 
consecutive women of reproductive age without any restriction to specific population 
(miscarriage, sub fertility, preterm births).  
Such descriptions raise the question: why the authors have not included patients without any 
reproductive failures, if the study was addressed to women with septate uterus? It is the most 
appropriate population for generalizabil ity of the results for women with septate uterus.  
 
(II) the used definition of septate uterus  
 
Crucial to any study on congenital anomalies and septate uterus is the understanding of the 
definitions and the relevance/appropriateness of the criteria used.  
 
The specific definitions of septate uterus according to the all versions of protocol should be 
included in the method section.  
 
There is not justification to generalize the study results on the ESHRE -ESGE criteria 
(discussion), if these criteria were not  used prospectively for selection of consecutive patients for 
the study (!) (it is impossible to accurately re -classify the results using the ESHRE -ESGE criteria 
without the use of 3D US datasets or MRI in all cases).  
 
The aplication of the ESHRE -ESGE def inition in consecutive women of reproductive age 
reflects mainly uterine wall thickness, whereas the ESHRE -ESGE definition does not reflect the 
presence of any septum in most cases assessed consecutively.  
 
Hysteroscopic metroplasty is a lucrative procedur e for many centers and doctors, therefore it is a 
great risk that one will  be performed on a healthy uterus having been labelled as septate 
according to the ESHRE -ESGE invalid definition, if the study shows the benefits of metroplasty. 
The authors should consider that it is a high risk that over 20% of unselected women and 80% 
women with the presence of an internal fundal indentation may fulfill the ESHRE criteria of 
septate uterus. The median uterine wall thickness according to the recent ESHRE -ESGE 
defin ition is 7mm and a septate uterus can be recognized in women with the median of an 
internal indentation equaling 3.6mm.  
  
According to available recent study  (The CUME study, 2017) the quoted definition (ESHRE -
ESGE definition of septate uterus) should be  considered as iatrogenic, as such a definition 
reflects mainly normal/arcuate uterus according to independent experts' opinions.  
 
I speculate that use of the ESHRE -ESGE criteria is rather declarative and it has been quoted as 
an insight rather than factua lly based, the authors should be able to recognize the problem with 
the inaccuracy of such criteria in comparison to the subjective impression of experienced doctors 
whom participated in the study. It seems, that as in all studies without true measurements , the 
diagnosis in the TRUST trial is based on subjective judgments of experienced doctors, which 
should be highlighted, if it is true.  
 
(III) the used diagnostic tests  
 
The used diagnostic tests for septate uterus should be referred to including the first  version of the 
protocol and all modifications. Inaccurate tests should be quoted in the manuscript, as they were 
used systematically.  
Version 1: HSG  
 
(IV) the assessment of the uterine morphology after healing period; second look hysteroscopy; (it 
was de scribed/registered in the initial version of the protocol), therefore readers want to know 
about the criteria of qualifications for a secondary surgery if a residual septum was present. The 
authors should explain whether they performed secondary surgeries or not. It is well known that 
a significant part of septate uteri after metroplasty are still septate uteri (even after a complete 
resection due to healing, especially using the ESHRE -ESGE criteria; Ludwin et al., Human 
Reprod 2014).  
 
It should be decribed in the method section; yes/not; rationale  
 
 
(V) the overinterpretation of the quality of the used methodology in the manuscript regarding 
further generalizability of the study results and the used definition of septate uterus should b e 
avoided: the definition of septate uterus used in the study was not reliable nor accurate, the 
population consists of three different cohorts (i) recurrent miscarriages, (ii) recurrent 
miscarriages + subfertility, (iii) miscarriage + subfertility + prete rm birth and their time -
dependent inclusions due to the impossibility of finishing the original TRUST protocol (adressed 
only to women with recurrent miscarriages and presence of the septum).  
 
 
 SPECIFIC COMMENTS  
 
Line 75 -76 I suggest adding the tradition al anatomic definition of septate uterus (ie. a uterus with 
a single uterine fundus and with a uterine cavity divided into two parts; AFS, ASRM Fertil Steril 
2016; or 'A septate uterus is an inborn abnormality of the uterus (womb), where the womb is 
divide d into two cavities' Rikken et al., 2017 Cochrane).  
 
Line 130 -135 The changed definition is significantly different than registered definitions.  
 
I strongly recommend including in the manuscript the registered definition per specific period 
and versions;  
According to the registry the septate uterus was/is definied as;  
Version 1  
Version 2  
Currently the registered definition of the septate uterus is:  
 
Version 6 December 2015: 'A septate uterus is defined as a uterus with a division (septum) of the 
uterine c avity, without any restrictions to the length of the septum. The external contour of the 
uterus should not have an indentation.' Should be kept as in the original version of the 
manuscript.  
 
This definition doesn't reflect the ESHRE -ESGE definition. Moreov er, the use of the ESHRE -
ESGE definition using this reference was impossible; CONUTA did not know how and when the 
uterine wall thickess should be measured.  
 
Line 141 -144 I suggest adding information about HSG, which was the most important method 
for class ification of the septate uterus in the first period of the study.  
 
 
Line 238 -240 I don't agree with this statement. The calculation was based on data from women 
with recurrent miscarriages and septate uterus by the AFS definition. The sample size should be  
re-calculated according to the results from studies/metaanalysis with a mixed population. It is 
easy to compare. I suggest doing it. I doubt that the study design is appropriate for general the 
question (septate uterus) as was explained, yet I realize tha t after ten years it is ‚pragmatic' RCT 
and the main goal is finishing the study.  
 
Line 243 -245 I think that such reclassification is controversial and inaccurate because with the 
used diagnostic tools (laparoscopy, hysteroscopy, HSG, 2D saline infusion s onohysterography) 
we cannot measure the uterine wall thickness according to the ESHRE -ESGE definition (the 
distance between the interostial line and the external contour of the uterus). However, I suggest 
re-classifiying the results according the ASRM 2016 , and specifically using the CUME 
definition (a resonable reference standard from a validation study) based on measurements of the 
internal indentation depth (if these data are available for re -assessment).  
 
If authors want to keep this statement; ‚We have changed the definition of the septate uterus 
according to new insights leading to the ESHRE ESGE classification, retrospectively all women 
meet these new criteria'  
I suggest adding: 'and may also meet the A SRM criteria for both normal/arcuate and septate 
uterus'.  
 
At this time I believe that the most appropriate step is the validation of the study results by the 
CUME definition.  
There are not reasonable scientific grounds to prefer the ESHRE -ESGE relative t o ASRM for 
validation of the used definitions in the study; ESHRE -ESGE highly overestimates and ASRM 
underestimates the prevalence of septate uteri in comparison to CUME - the most voted option 
by experts therefore implementing the CUME definition is the b est optimal choice.  
 
RECOMMENDATION FOR PROTOCOL/REGISTRY  
 
To avoid the use of the arbitrary definition, as suggested by ESHRE -ESGE or ASRM (despite of 
that the ASRM definitions of normal/arcuate, septate, and bicornuate uterus based on assessment 
of avail able literature), I suggest registering a reasonable reference standard based on the CUME 
definition (1cm) as eligible criterion to study (Ludwin et al, Ultrasound Obstet Gynecol 2017); 
other criteria are totally arbitrary thus may be considered as iatroge nic and even dangerous for 
patients (ESHRE -ESGE; surgical harming of healthy uterus). Using of the ESHRE -ESGE 
criteria according to current knowledge may be an ethical issue; IRB should be informed that 
such criteria have never been used in patient managem ent and it is well known that these criteria 
labelled as septate are normal and arcuate uterus in the most patients.  
 
Reference:  
 
Ludwin A, Martins WP, Nastri CO, Ludwin I, Coelho Neto MA, Leitão VM, Acién M, Alcazar 
JL, Benacerraf B, Condous G, De Wilde RL, Emanuel MH, Gibbons W, Guerriero S, Hurd WW, 
Levine D, Lindheim S, Pellicer A, Petraglia F, Saridogan E. Congenital Uterine Malformation by 
Experts (CUME): better criteria for distinguishing between normal/arcuate and septate uterus. 
Ultrasound Obstet Gynecol. 2017 Oct 11. doi: 10.1002/uog.18923.  
 
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.  
I am able to assess the statistics  
Quality  of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
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