Prospective Validation of the ADNEX Model for Discrimination Between Benign and Malignant Adnexal Masses in Pregnancy: the International Ovarian Tumour Analysis in Pregnancy Study (p-IOTA).
Conditions: Adnexal Mass, Adnexal Tumor, Adnexal Cyst, Pregnancy Related
Sponsor: Universitaire Ziekenhuizen KU Leuven

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Prospective Validation of the ADNEX Model for discrimination between benign 
and malignant adnexal masses in pregnancy: 
International Ovarian Tumour Analysis in pregnancy study (p-IOTA) 
 
 
Sponsor 
KU Leuven is the main research sponsor for this study. 
UZ/KU Leuven  
Herestraat 49 
3000 Leuven 
Belgium  
 
Principal Investigator: prof. dr. Wouter Froyman 
UZ Leuven department Gynaecology and obstetrics 
KU Leuven Departement Ontwikkeling en Regeneratie 
 
 
Chief Investigator:  Srdjan Saso  
Dr Srdjan Saso BSc MRCS MRCOG PhD 
Consultant in Gynaecology and Gynaecological Oncology 
Department of Gynaecological Oncology 
Honorary Clinical Senior Lecturer, Institute of Reproductive and Developmental Biology 
Imperial College London 
Phone: +447890795182; E-mail: Srdjan.saso@imperial.ac.uk 
https://www.imperial.ac.uk/people/srdjan.saso01 
Twitter: @SasoGynaecology 
 
The list below contains potential investigators that have expressed their interest and is 
not exhaustive. Other centres may be included on condition that they fulfil the criteria for 
this study and on condition of approval by their local Ethics Committee 
 
IOTA Steering Committee 
• 
Dirk Timmerman, University Hospital KU Leuven, Belgium (co-ordinator) 
• 
Tom Bourne, Imperial College, London and KU Leuven 
• 
Lil Valentin, Skåne University Hospital Malmö, Lund University, Malmö, Sweden 
• 
Ben Van Calster, KU Leuven University, Belgium 
• 
Antonia Testa, Università Cattolica del Sacro Cuore, Rome, Italy 
• 
Wouter Froyman, University Hospital KU Leuven, Belgium 
• 
Ignace Vergote, University Hospital KU Leuven, Belgium 
• 
Sabine Van Huffel, KU Leuven University, Belgium 
 

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p-IOTA Management Committee 
 
London, UK 
 
Dr Srdjan Saso BSc MRCS MRCOG PhD 
Department of Gynaecological Oncology 
Honorary Clinical Lecturer, Institute of Reproductive and Developmental Biology 
Imperial College London 
Phone: +447890795182; E-mail: Srdjan.saso@imperial.ac.uk 
https://www.imperial.ac.uk/people/srdjan.saso01 
Twitter: @SasoGynaecology 
 
Tom Bourne, MD, PhD 
Professor, Queen Charlotte’s & Chelsea Hospital, Imperial College NHS Trust 
Early Pregnancy and Acute Gynaecology Unit, Queen Charlotte's & Chelsea Hospital 
Du Cane Road, London W12 0NN, UNITED KINGDOM 
Phone: +44 (0)20 3313 5131 ; E-mail: womensultrasound@btinternet.com 
 
Maya Al-Memar, PhD, MRCOG 
Consultant, Queen Charlotte’s & Chelsea Hospital, Imperial College NHS Trust 
Early Pregnancy and Acute Gynaecology Unit, Queen Charlotte's & Chelsea Hospital 
Du Cane Road, London W12 0NN, UNITED KINGDOM 
Phone: +44 (0)20 3313 5131 ; E-mail: maya.al-memar@hotmail.com  
 
Leuven, Belgium 
 
Dirk Timmerman, MD, PhD, FRCOG 
Professor, Department of Obstetrics and Gynaecology  
University Hospitals KU Leuven,  
Herestraat 49, B-3000 Leuven, BELGIUM  
Phone: + 32 16 344201 (office) 
 
 
Fax: + 32 16 344205 (office) 
E-mail: dirk.timmerman@uzleuven.be 
 
Professor Wouter Froyman, MD, PhD 
Department of Obstetrics and Gynaecology  
University Hospitals KU Leuven,  
Herestraat 49, B-3000 Leuven, BELGIUM  
Phone: + 32 16 344201 (office) 
 
 
Fax: + 32 16 344205 (office) 
E-mail: wouter.froyman@uzleuven.be 
 
Malmo, Sweden 
 
Lil Valentin, MD, PhD, FRCOG 
Senior Professor, Department of Obstetrics and Gynaecology 
Skåne University Hospital Malmö, E20502, Malmö, SWEDEN.  
(home address: Lövviksg 7B, 21374 Malmö) 
Mobile Phone: +46 709 416 156 
 
 

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Phone: +46 40 332149 or 332094 (office) 
             Fax: +46 40 962600 (office) 
E-mail: lil.valentin@med.lu.se 
 
Rome, Italy 
 
Antonia Carla Testa, MD, PhD 
Unità Operativa di Ginecologia Oncologica Dipartimento Tutela della Salute della Donna e della 
Vita Nascente Università Cattolica di Sacro Cuore  
Largo Agostino Gemelli 8, Roma, ITALY 
Phone: +39 06 30156399; Mobile: +39 339 7044256; Fax: +39 06 35510031 
E-mail: testa.antonia@gmail.com 
 
Francesca Moro, MD, PhD 
Dipartimento Scienze della Salute, del Bambino e di Sanità Pubblica. 
Fondazione Policlinico Agostino Gemelli, Rome, Italy 
L.go A. Gemelli 8, 00168 Rome, Italy 
Phone: +39 0630156399; E-mail: morofrancy@gmail.com; 
 
Floriana Mascilini, MD, PhD 
Dipartimento Scienze della Salute, del Bambino e di Sanità Pubblica. 
Fondazione Policlinico Agostino Gemelli, Rome, Italy. 
L.go A. Gemelli 8, 00168 Rome, Italy 
Tel: +39 0630156399; E-mail: floriana_mascilini@hotmail.com  
 
Chiara Landolfo MD, PhD  
Dipartimento Scienze della Salute, del Bambino e di Sanità Pubblica. 
Fondazione Policlinico Agostino Gemelli, Rome, Italy. 
L.go A. Gemelli 8, 00168 Rome, Italy 
E-mail: chiara.landolfo@gmail.com   
 
 
Investigators already involved in previous IOTA phases  
 
RIT 
Antonia Carla Testa, MD, PhD 
Polo Tutela della Salute della Donna e del Bambino.  
Fondazione Policlinico Universitario Agostino Gemelli 
Largo Agostino Gemelli 8, Roma, ITALY 
Phone: +39 06 30154979 
Mobile: +39 339 7044256 
Fax: +39 06 35510031 
E-mail: testa.antonia@gmail.com 
 
CIT 
Dorella Franchi, MD, PhD 
Unità di Ginecologia preventiva  
Istituto Europeo Oncologia 
Via Ripamonti 435, 20141 Milan, ITALY 

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Phone: +39 3492847455 
Mobile: +39 3492847455 
Fax: +39 0294379243 
E-mail: dorella.franchi@ieo.it 
 
IUK 
Tom Bourne, MD, PhD 
Queen Charlotte’s & Chelsea Hospital 
Imperial College London 
Early Pregnancy and Acute Gynaecology Unit, Queen Charlotte's & Chelsea Hospital 
Du Cane Road, London W12 0NN, UNITED KINGDOM 
Phone: +44 (0)20 3313 5131 
E-mail: womensultrasound@btinternet.com 
 
LPO  
Artur Czekierdowski, MD, PhD 
Department of Gynecological Oncology and Gynecology, Medical University of Lublin 
16 Staszica Str., 20-081 Lublin, POLAND  
Telephone: +4881 532 78 47  
 
 
Fax: +4881 532 06 08 
E-mail: artur.czekierdowski@uml.edu.pl 
 
SSW 
Elisabeth Epstein, MD, PhD 
Department of Clinical Science and Education, Södersjukhuset (KI-SÖS) 
118 83 Stockholm, SWEDEN 
Department of Obstetrics and Gynaecology, Karolinska University Hospital 
S- 171 76, Stockholm, SWEDEN  
Phone: +46-8-51779958 
mail: elisabeth.epstein@sll.se 
 
PCR 
Daniela Fischerová, MD, PhD 
Gynaecological Oncology Centre, Department of Obstetrics and Gynaecology, Charles University, 
Prague, CZECH REPUBLIC 
Telephone: +42 0603285097 (mobile) 
E-mail: daniela.fischerova@seznam.cz  
 
LBE 
Dirk Timmerman, MD, PhD 
Wouter Froyman, MD 
Chiara Landolfo, MD 
Professor and clinical head, Department of Obstetrics and Gynaecology,  
University Hospitals KU Leuven,  
Herestraat 49, B-3000 Leuven, BELGIUM.  
Telephone: + 32 16 344201 (office) 
 
 
Fax: + 32 16 344205 (office) 
E-mail: dirk.timmerman@uzleuven.be 
 
MSW 

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Lil Valentin, MD, PhD 
Povilas Sladkevicius, MD, PhD 
Department of Obstetrics and Gynecology 
Skåne University Hospital Malmö 
SE20502 Malmö, SWEDEN.  
(home adresse: Lövviksg 7B, 21374 Malmö) 
Mobile Phone: +46 709 416 156 
 
 
Phone: +46 40 332149 or 332094 (office) 
             Fax: +46 40 962600 (office) 
E-mail: lil.valentin@med.lu.se 
 
PSP 
Juan-Luis Alcazar, MD 
University of Navarra 
Pamplona, Spain 
E-mail: jlalcazar@unav.es 
 
Potential additional Principal Investigator 
Jessica Preisler, Chile 
Nguyen Ha, Vietnam 
Mala Sibal, India 
Susanne Johnson, UK 
Georges Condous, Australia 
Dusan Djokovic, Portugal 
Margarita Medina-Castellano, Spain 
Lilit Hovsepyan, Armenia 
Potential Dutch centres 
Jeroen Kaijser, Kazia Ziekenhuis 
Sandrine Lambregts, MUMC 
Hanny Pijnenborg, Radboud Nijmegen 
Christianne Lok, Antoni v Leeuwenhoek ziekenhuis 
Peggy Geomini, Maxima Medisch centrum 
 
Potential Italian centres 
Francesca Buonomo, Trieste 
Elisa Mor, Brescia 
Cinzia Baima, Torino 
Robert Fruscio, Monza 
 
 

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Table of Contents 
 
1. 
Study Summary 
 
2.  
Background 
 
 
3. 
Study Objectives 
 
4. 
Study Design and Setting 
 
 
4.1 Study centres 
 
 
4.2 Design 
 
 
4.3 Duration 
 
5.  
Patients 
 
 
5.1 Inclusion criteria 
 
 
5.2 Exclusion criteria 
 
 
5.3 Withdrawal criteria 
 
 
5.4 Consent and information leaflet 
 
6.  
Method and Documentation 
 
6.1 General Process 
6.2 Study flow 
6.3 Definition of level of ultrasound experience   
6.4 Surgical intervention during follow-up 
6.5 Study Closure 
6.6 Documentation and Communication 
 
 
7.  
Study Outcome Measures 
 
 
7.1 Primary Outcomes Measures 
 
 
7.2 Secondary Outcome Measures 
 
 
7.3 Tertiary Outcome Measures 
 
 
8.  
Study Population and Sample Size 
 
9.  
Study Supervision and Monitoring 
 
10. 
Regulatory Issues 
 
11.  
References  
 
12.  
Appendices  
 
Appendix 1 - Ultrasound examination IOTA terms and definitions 
 
Appendix 2 - Data recorded at inclusion scan  
 
Appendix 3 - Data recorded at follow-up scan  
 
Appendix 4 - Data recorded at 0-90 days postpartum scan 
 
Appendix 5 - Outcomes (non-ultrasound) 
 
Appendix 6 - Data Processing Annex (DPA) 

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1. STUDY SUMMARY  
 
TITLE  
Prospective Validation of the ADNEX Model for discrimination between benign and malignant 
adnexal masses in pregnancy: the International Ovarian Tumour Analysis in pregnancy study 
(p-IOTA). 
 
DESIGN  
Multicentre, prospective cohort observational study. 
 
BACKGROUND 
Adnexal masses are a common incidental finding in pregnancy.  Whilst the majority are benign 
and resolve spontaneously, a proportion can exhibit suspicious features during pregnancy 
raising concern about an underlying malignancy. Correct classification of adnexal masses is 
particularly important during pregnancy given the potential foetal and maternal risks 
associated with surgical intervention. International Ovarian Tumour Analysis (IOTA) group 
have developed robust, ultrasound-based tools, including the ADNEX model to support the 
classification of adnexal masses. Ultrasound-based tools such the Modified Benign Simple 
Descriptors and ADNEX have been externally validated to aid in the classification of adnexal 
masses in non-pregnant women, but their use as a robust diagnostic tool in pregnancy remains 
to be demonstrated.  
 
AIMS  
The principal objective of this study is to prospectively investigate the ability of the ADNEX 
Model and a 2-step strategy (i.e. Modified Benign Simple Descriptors followed by ADNEX) to 
correctly discriminate between benign and malignant adnexal masses diagnosed in pregnancy. 
 
PRIMARY OUTCOME MEASURE 
False discovery rate (number of benign masses / number of masses classified as malignant) 
when using the ADNEX Model to discriminate between benign and malignant adnexal masses at 
11-14 gestational weeks in pregnancy. 
 
ELIGIBILITY 
All women 18 years old and above with an adnexal mass found on ultrasound scan during 
pregnancy - irrespective of whether the mass known before pregnancy OR diagnosed for the 
first time on ultrasound scan during pregnancy. 
  
DURATION 
This study will be conducted over a minimum period of three years. 
 
KEYWORDS 
IOTA, ovarian mass, benign, malignant, ultrasound, pregnancy, post-partum 
 
 
 
 
 

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2. BACKGROUND 
 
Ovarian masses 
Ovarian masses are common in women of reproductive age and are often found incidentally on 
ultrasound in asymptomatic women. The majority of ovarian masses are benign, and thus do not 
require removal. Yet, 1 in 10 women will undergo surgery in their lifetime for the removal of an 
ovarian cyst1. The decision to proceed with surgical management is for two main reasons. First, 
because of concern regarding malignancy potential and second, to reduce the risk of or treat 
complications associated with adnexal masses such as cyst rupture or ovarian torsion.  
 
In pregnancy, the integration of routine first trimester ultrasound as part of antenatal screening 
has led to an increased detection rate of adnexal masses. The prevalence of adnexal masses in 
pregnancy varies widely2,3. The vast majority of adnexal masses identified in pregnancy are benign 
physiological cysts which resolve spontaneously without any intervention. Goh et al analysed 
24,868 pregnancies, identifying 1225 ovarian masses, of these only 171 (0.7%) had a persistent 
ovarian mass ≥5cm2.  
 
Cancer is estimated to complicate 1 in 1000 pregnancies, but is on the rise, largely driven by an 
increase in women choosing to delay starting a family into their thirties4. Ovarian malignancy is 
one of the top five cancers identified in pregnancy. A recent, large international cohort identified 
1170 women diagnosed with primary cancer during pregnancy, of those 88 (7%) had ovarian 
cancer (primary invasive and borderline ovarian tumours - type not specified)5. The majority of 
women diagnosed with ovarian cancer in pregnancy had stage I disease (>70%). Ovarian cancer, 
although on the rise, remains uncommon in women of reproductive age. In a large US cohort 
consisting of 9375 adnexal masses identified in pregnancy, the rate of ovarian cancer (n=87) and 
BOTs (n=115) were 0.93% and 1.2% respectively6. It is worth highlighting that the definition of 
cancer Is not always precisely defined in each study.   
 
IOTA: Ultrasound-based tools  
The balance between surgical and expectant management is underpinned by confidence in correct 
characterization of ovarian masses. If one can confidently characterise the mass as benign, then 
expectant management is a safe strategy, given that the overall risk of torsion or cyst accident is 
low7.  
 
The use of ultrasound-based tools, such as Simple Descriptors, Simple Rules, ADNEX model, IOTA 
LR2 model and Simple Rules Risk estimation model, have been widely validated across multiple 
centres, in the hands of expert and non-expert ultrasound examiners8-15. These tools were validated 
to ensure their robustness to aid in the correct characterization of ovarian masses. ADNEX model 
incorporates six ultrasound characteristics: number of papillary projections (0, 1, 2, 3 or more than 
3), number of cyst locules (10 vs. >10), presence of acoustic shadowing (yes/no), diameter of 
largest solid component (mm), largest diameter of adnexal lesion and ascites (yes/no). The ADNEX 
model is not only able to differentiate between benign and malignant, but also has the capability to 
sub-divide into the risks of specific types/stages of malignancy, including borderline, Stage I, Stage 
II-IV or metastases15.   
 
Simple rules method uses ten ultrasound features seen in benign masses (B-features) and 
malignant masses (M-features)16. The ‘M’ features include irregular solid tumour, presence of 

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ascites, 4 or more papillary projections, irregular multilocular solid tumour with largest diameter 
100mm and very strong blood flow (Doppler colour score of 4). The ‘B’ features include unilocular 
mass, presence of solid components with largest diameter < 7mm, presence of acoustic shadowing, 
smooth multi-locular tumour with largest diameter < 100mm and no blood flow (Doppler colour 
score of 1)16.  In cases where neither M or B rules apply, or where both are present, the mass is 
classified as ‘unclassifiable’ and further investigations are required.  
 
Recognising the importance of correct characterization of ovarian masses, the Royal College of 
Obstetricians and Gynaecologist (RCOG) has integrated the ‘Simple Rules’ tool into national 
guidance for use in the management of ovarian masses in pre-menopausal women1. The IOTA 
group has also evaluated the behaviour of ovarian masses, characterised as benign, over a period of 
two years. The aim of the study was to further the overall understanding of the natural history of 
various adnexal mass sub-types and the incidence of complications such as malignant 
transformation, ovarian torsion and cyst accident. This was done to determine whether expectant 
management of adnexal masses represents a safe option. Overall, the data was reassuring with only 
0.7% of masses displaying malignancy (i.e. false-negative results of initial scan or malignant 
transformation; 0.3% were borderline ovarian tumours), 0.4% ovarian torsion and 0.2% cyst 
rupture7 (the reported incidences are cumulative).  The low cumulative incidence of observed 
complications reinforces ‘expectant’ management as a safe, robust strategy for managing women 
with benign adnexal masses.  
 
Tumour markers have some role in the characterisation of adnexal masses. Cancer antigen-125 
(CA125) was identified as a screening/triage tool to identify women at risk of ovarian cancer in 
primary care. The aim was to enable prompt referral into tertiary care. It is a significant contributor 
to the Risk of Malignancy Index (RMI)17,18. CA125 has been shown to have more value in 
discriminating between benign and malignant masses in post-menopausal than pre-menopausal 
women19,20. CA125 is elevated in numerous gynaecological conditions including endometriosis and 
infections. In pregnancy, CA125 is produced by amnion cells and decidua during foetal 
development, so is typically elevated particularly in the first trimester. In early-stage ovarian 
cancer, 1 in 2 women will have a normal CA12521. Given CA125 is elevated in pregnancy and 
pregnant women typically present with stage I disease, it is likely to have limited clinical value as a 
tumour marker in pregnancy22. 
 
Adnexal Masses and Pregnancy 
The natural history and behaviour of adnexal masses have not yet been explored in pregnancy and 
the post-partum period using large prospective patient cohorts. Pregnancy is a unique situation. 
First, it provides a group of women who will be scanned during the antenatal period, allowing for 
an opportunity to prospectively follow-up adnexal masses at distinct time points in pregnancy. 
Second, because of the potential risks of surgery (maternal and foetal) in pregnancy, women are 
more inclined to be managed conservatively. This generates a large cohort of women undergoing 
expectant management of adnexal masses. This gives us a possibility to improve our understanding 
of the natural history of adnexal masses during pregnancy.  
 
The higher stakes in pregnancy (i.e. health of mother and baby) reinforce the importance of correct 
interpretation of ultrasound images. In particular, the potential value of using an ultrasound-based 
tool to aid in the characterisation of adnexal masses in pregnancy is evident. No ultrasound-based 
tools have yet been validated for use in pregnancy. Therefore, a clear need exists for a robust, 

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validated ultrasound tool to facilitate the correct characterization of adnexal masses in pregnancy. 
In turn, this will ensure appropriate management and importantly, surgical intervention only for 
women with a high index of suspicion of malignancy or clinical complications associated with an 
adnexal mass. In order to inform safe management of adnexal masses in pregnancy, it is first 
paramount that we further our understanding about the normal trajectory of adnexal masses 
during pregnancy and the postpartum period.  
 
The majority of women identified as having an adnexal mass at 12-14 weeks have a pregnancy-
associated physiological cyst, such as a follicular, corpus luteum or a haemorrhagic cysts23.  The 
majority of cysts identified at first trimester ultrasound resolve spontaneously by 18-20 weeks24. 
Adnexal masses which persist beyond 16-20 weeks suggest an underlying pathology. The rate of 
spontaneous resolution was shown to be much lower if the adnexal mass was more than 5cm or 
complex in ultrasound appearance23.  
 
Dermoid cysts (mature teratomas) are the commonest ovarian masses seen in women beyond 16 
weeks’ gestation. Malignant transformation can occur, most commonly to an invasive squamous 
carcinoma25,26,27. Dermoid cysts have typical features on ultrasound including hyperechoic nodules, 
acoustic shadowing, hyperechoic lines or a fluid level28. Outside of pregnancy, dermoid cysts have 
been shown to be slow growing, with a mean growth rate of 1.67-1.8 mm per annum29. In a 
prospective study of dermoid cysts in pregnancy, they were not shown to significantly increase in 
size and no complications such as cyst rupture or torsion occurred27.  
 
Borderline ovarian tumours (BOTs) are more common in women of child-bearing age with a third 
diagnosed in women <40 years old30. BOTs account for up 3-8% of adnexal masses diagnosed in 
pregnancy31. They are the most frequent type of ovarian malignancy encountered in pregnancy. A 
multi-centre French retrospective study focusing on the diagnosis and management of BOTs in 
pregnancy showed that 90% of women underwent surgery. 20% were identified as having Stage II 
disease and were noted to have a higher incidence of invasive, aggressive patterns of disease than 
non-pregnant counterparts32. The ultrasound appearances of BOT can overlap with the changes 
that occur in endometriomas during pregnancy, making the distinction between benign and 
malignant masses more challenging in pregnancy33.   
 
Endometriomas represent 4-8% of ovarian cysts identified during routine sonography in the first 
trimester31,34. In pregnancy, the endometrium undergoes ‘decidualisation’. This is a process 
associated with an increase in glandular epithelium and stromal vascularity, occurring to optimise 
endometrial receptivity in preparation for embryo implantation35. A similar process occurs within 
ectopic endometrial tissue within the walls of endometriomas. Decidualisation has the appearance 
of solid, vascular areas, within the wall of an endometrioma on ultrasound, which can raise a 
suspicion of malignant transformation and results in unnecessary surgical intervention in many 
cases36. 
 
Decidualisation is a transient, dynamic process that occurs during pregnancy and differs from the 
irreversible neoplastic changes that occur within malignant tumours. The decidualisation process 
does not occur in every endometrioma. A retrospective study of 34 endometriomas in pregnancy 
demonstrated it only occurred in 12% of endometriomas35. 
 

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Furthermore, the solid areas within an endometrioma, which has undergone the process of 
decidualisation, can mimic the appearance of papillary projections. Papillary projections are 
features commonly associated with malignant tumours, particularly BOTs. Recognising the changes 
that pregnancy has on the ultrasound appearance of adnexal masses, Mascilini et al carried out a 
retrospective review of 34 women in pregnancy who underwent surgical removal of an ovarian 
cyst with papillary projections, but no other solid components. The study found that the presence 
of a smooth contour of papillations (79% vs 27%) and ground glass echogenicity (74% vs. 13%) 
were more commonly seen in benign than malignant adnexal masses36. Whilst Mascilini et al 
helped to improve the understanding of sonographic appearances of specific adnexal mass 
features, such as solid areas during pregnancy, a need exists for a prospective evaluation of adnexal 
masses at distinct time points during pregnancy in order to delineate the timing and pattern of 
change through pregnancy and into the post-partum period. A particular area of interest is the 
decidualisation process that occurs within endometriomas, and how the appearance of the solid 
areas may change during pregnancy. Understanding the pattern of ‘physiological’ changes within 
the ovary during pregnancy will facilitate the detection of an underlying malignant transformation 
process within an adnexal mass. This will, therefore, facilitate the distinction between a benign and 
malignant mass.  Also of interest is the difference, if any, between the morphological appearance of 
invasive ovarian tumors, and metastases to the ovaries from primary tumours located somewhere 
else diagnosed during pregnancy37,38. 
 
Expectant versus Surgical management during pregnancy 
Traditionally, because of the overall concern about the potential risks of complications relating to 
persistent ovarian cysts in pregnancy, routine surgical removal was recommended. Practice has 
now changed in favour of expectant management of adnexal masses which appear benign on 
ultrasound.  This is primarily because of the maternal/foetal risks associated with undergoing 
surgery during pregnancy, combined with a low incidence of complications, such as ovarian 
torsion, cyst rupture or malignant potential during pregnancy. Hence, expectant management 
appears to be a logical management strategy of adnexal masses in pregnancy.  
 
Surgical intervention may be required acutely if suspected torsion/cyst accident. Pregnancy is 
thought to increase the risk of ovarian torsion due to ovarian displacement secondary to uterine 
enlargement, (19.9% in pregnancy vs. 9% non-pregnancy)39,40. The rate of torsion varies widely but 
does appear to be proportional to the size of the adnexal mass, with larger masses more likely to 
undergo torsion or rupture24. Torsion tends to occur between 10 and 17 weeks and rarely beyond 
20 weeks24. The hypothesis here is that the gravid uterus restricts the mobility of the adnexa. 
 
Despite a low risk of an ovarian malignancy in pregnancy, a large number of women undergo 
surgery during pregnancy because of the concern for a potential malignant adnexal mass41. A 
retrospective study by Yen et al evaluated the risk of malignancy in a cohort of women who were 
identified as having an adnexal mass and underwent surgical management during pregnancy or at 
the time of delivery. The frequency of ovarian cancer within the cohort was 2.3%, which is 
reassuringly low42. In a study by Schmeler et al, of the 63 patients diagnosed with a mass >5cm, 17 
required surgery during pregnancy, 13 due to suspicious ultrasound findings and 4 due to acute 
pain suggestive of torsion43. Four patients had a histological diagnosis of ovarian cancer but the 
remainder had a benign diagnosis, most commonly a dermoid cyst43. 
 

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The use of ultrasound as first line imaging modality in pregnancy was reinforced by Moro et al, who 
demonstrated that the ultrasound features of malignant ovarian masses in women (n=22) scanned 
prior to surgical intervention of a mass were consistent to those seen outside of pregnancy37. 
Surgical intervention is preferably avoided in pregnancy due to the potential maternal and foetal 
risks44. The rate of non-obstetric surgery was 0.73% in a large retrospective cohort study of 6.5 
million pregnancies45. Although surgery is perceived as relatively safe in pregnancy, a recent 
retrospective cohort study by Balinskaite et al, observed an increase in low birth weight (<2.5Kg), 
preterm delivery (<37 weeks) and foetal growth restriction in women who underwent surgery 
compared to those that did not45. Women who underwent laparoscopic procedures, which 
required hospitalisation were shown to have a higher rate of miscarriage than those who 
underwent open abdominal surgery46. A laparoscopic approach, however, is generally preferred, 
due to better post-op recovery, less opioid use, reduced basal lung atelectasis, minimal uterine 
manipulation and a lower incidence of venous thromboembolism (VTE) events24.  
 
Taking the potential maternal and foetal risks of surgery into account, combined with the inherent 
low risks of complications in association with adnexal masses, expectant management is the 
preferred management approach for adnexal masses in pregnancy. In addition, it is important to 
highlight that assessing the adnexal mass at 11-14 weeks gestation allows us to plan for minimally 
invasive surgery if necessary. Surgery before this period would coincide with a time in gestation 
where risk of miscarriage is at its highest45. After 11-14 weeks, risk of miscarriage falls. Therefore, 
if surgery is deemed necessary, it is preferably performed between 14 and 20 weeks. Risks of 
surgery increase after 20 weeks, although if necessary, surgery is feasible throughout pregnancy45.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. STUDY OBJECTIVES 
 
Primary objective 
 
- 
To prospectively validate the ability of the ADNEX Model to discriminate between 
benign and malignant adnexal masses at 11-14 weeks gestation. 
 
Secondary objectives  
 
- 
To prospectively validate the ability of the 2-step strategy (i.e. Modified Benign Simple 
Descriptors followed by ADNEX) to discriminate between benign and malignant adnexal masses 
at 11-14 weeks gestation; 
- 
To prospectively validate the ability of the ADNEX Model and the 2-step strategy (i.e. 
Modified Benign Simple Descriptors followed by ADNEX) to discriminate between benign and 
malignant adnexal masses when first detected at any time point in pregnancy (irrespective of 
whether the mass was known before pregnancy or detected for the first time during 
pregnancy); 
- 
To longitudinally examine the development of an adnexal mass during pregnancy with 
description of final outcome, based on scans performed at pre-specified time points and scans 
added as a result of a clinical decision. 
 
Tertiary objectives 
 
- 
To describe the evolution of endometriomas during gestation; 
- 
To study the occurrence of complications such as rupture, torsion, or malignancy during 
pregnancy in patients with conservatively treated masses; 
- 
To compare the performance of the ADNEX model with CA125 with that of ADNEX without 
CA125; 
- 
To suggest an IOTA triaging system on the basis of the results of the study which may be 
applied to guide management during pregnancy; 
- 
To collect images, clips and volumes for quality control, illustration of changes during 
pregnancy, educational purposes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. STUDY DESIGN AND SETTING 
 
4.1. Study Centres 
 
The following type of unit/centre will be included: 
 
-  
Expert centres for ultrasound (with expertise as per definition described below) with 
or without an oncology department attached to it; 
- 
Early Pregnancy Units (EPUs) but only if capable on deciding management without 
referring to a tertiary referral centre (EPUs are defined as units which offer a service for women 
with symptoms such as pain or bleeding in early pregnancy <14 weeks and are run by 
gynaecologists). 
 
There will be: 
 
- A named individual in each participating Study centre responsible for coordinating the 
project locally and reporting directly to the p-IOTA Management Committee. 
 
- Regular inspection by the Chief Investigator (Dr Srdjan Saso) and the IOTA Study 
Manager (Mr Matt Malecki), will be carried out ensuring that both the service 
(communication, documentation, supervision and logistics) and facilities (ultrasound 
equipment and space) are of high standards.  
 
4.2 Study design 
 
Multicentre prospective cohort observational study 
 
4.3 Duration 
 
The study will be conducted over a minimum of three years. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5. PATIENTS 
 
5.1 Inclusion Criteria 
 
• 
Consecutive patients with non-physiological adnexal masses or physiological cysts 
measuring 5cm or more in largest dimension; 
• 
In case of more than one mass seen, only most suspicious mass to be included OR in case 
of two similar masses, the one with the largest dimension or most easily accessible with 
ultrasound; 
• 
Previously recruited patient presenting with a different mass in subsequent pregnancy; 
• 
Age 18 years and above. 
 
5.2 Exclusion Criteria 
  
• 
Cysts deemed to be clearly physiological WHEN smaller than 5 cm (largest diameter); 
• 
Non-adnexal masses, e.g. peritoneal inclusion cysts (when diagnosis is certain) and 
peritoneal carcinomatosis with no adnexal mass; 
• 
The denial or withdrawal of written informed consent; 
• 
Same cyst already recruited for p-IOTA in a previous pregnancy. 
• 
Age < 18 years 
 
5.3 Withdrawal Criteria 
 
Patients may withdraw from the study at any stage and all data captured in relation to their 
participation may be destroyed at their request. 
 
5.4 Consent and Information leaflet  
 
All participating patients will be consented prior to enrolment and will receive a full 
explanatory information leaflet. Signed participant consent will be obtained. The right of the 
participant to decline participation without giving reasons will be respected. After the 
participant has entered the study the clinician remains free to propose management different 
from the one specified in the protocol at any stage if he/she feels it is in the participant’s best 
interest. The reasons for doing so should be recorded. In these cases, the participants remain 
within the study for the purposes of follow-up and data analysis. All participants are free to 
withdraw at any time from the protocol treatment without giving reasons and without 
prejudicing further treatment. 
 
 
 
 
 
 
 
 
 

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6. METHOD and DATA COLLECTION 
 
6.1 General Process 
 
We plan an initial recruitment period of 36 months. Women will be recruited to p-IOTA if found 
to have an adnexal mass (either newly diagnosed or previously known) at an ultrasound 
examination performed at any gestational age. 
 
Patients will be managed as per local clinical guidelines specific to the case, with all clinical 
decisions taken by lead clinicians according to current policy and practice. If a patient consents 
to taking part in the study, the number of scans will be determined by the p-IOTA protocol. 
 
For patients managed surgically, no follow-up ultrasound examinations after surgery will be 
required. Follow-up for these women is arranged by their clinicians as per clinical practice.  
 
6.2 Study flow 
 
Figure 1-3 illustrate the study flow. 
 
First arm (primary objective - figure 1): Adnexal mass scanned at 11-14 weeks. If the 
decision is to manage the adnexal mass conservatively, the patient is to be re-scanned 
once more: 0 - 90 days postpartum. In addition, the patient will be asked to enter into the 
third arm of the study (see below) knowing that she can opt out from that arm at any 
point.  If she consents to participate in the third arm, she will participate in a series of 
longitudinal examinations as described for the third arm. 
 
All patients with a mass detected before 11 weeks will also be scanned at 11-14 weeks 
and can enter all three arms of the study. In this scenario, if more than one scan is 
performed during pregnancy before 11 weeks, only the first of several scans before 11 
weeks will be included for the second and third arms of the study (see below). 
 
Second arm (secondary objective - figure 2): Adnexal mass is seen for the first time 
during that pregnancy at any gestation. If the decision is to manage the adnexal mass 
conservatively, the patient is to be re-scanned once more: 0 - 90 days postpartum. For 
patients with a mass detected before 11 weeks, see also above (they will be re-scanned at 
both 11-14 weeks and at 0-90 days postpartum). 
 
In addition, the patient will be asked to enter into the third arm of the study (see below) 
knowing that she can opt out from that arm at any point. If she consents to this, she will 
participate in a series of longitudinal examinations as described for the third arm.  
 
Third arm (secondary objective - figure 3): Patients from the first and second arms 
who agree to enrol into the third arm i.e. longitudinal examination of an adnexal mass 
during pregnancy. For the purposes of the longitudinal evaluation, the time points for the 
ultrasound examination are:  
 

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- initial presenting scan if <11 weeks;  
- 11-14 weeks; 
- 16 week scan - endometriomas ONLY; 
- second trimester routine scan (18-22 weeks); 
- 30-34 weeks; 
- any additional scans during pregnancy which resulted in either conservative 
management with extra scans or surgical intervention (with reason for the extra scan or 
for surgery documented); 
- 0-90 days postpartum. 
 
If the decision is to operate after the scan at which the mass was first detected during 
pregnancy with no follow-up scans planned before surgery, the patient is included in the 
study with the final outcome being the histopathological diagnosis of the surgically 
removed mass (see next section). 
 
If the adnexal mass is not seen at a subsequent follow-up scan but has been replaced with a 
normal ovary, there is no need for further follow-up scans. The final outcome is benign. 
 
Patients enrolled into the study but who suffer miscarriage, ectopic pregnancy or intra-
uterine death can be included in the study using same criteria as above. 
 
Definition of final outcome 
 
The final outcome, for the purpose of the analysis, will be based on the pathology result 
after surgery. If surgery is not performed, the diagnosis assigned by the ultrasound 
examiner using subjective assessment at the 0-90 days postpartum scan will be used. If 
neither surgery nor a postpartum scan are performed, the final outcome is defined as 
‘uncertain’. We describe this in more detail below. 
 
The final outcome will be benign or malignant (borderline or invasive) and will be based on:  
 
1) Histological diagnosis of the mass, if surgery performed during pregnancy OR within 120 days of 
the postpartum ultrasound scan  
 
If surgery is performed more than 120 days after the postpartum scan the histological diagnosis 
will be the final diagnosis only if the histological outcome is benign.  
 
If surgery is performed before a scheduled postpartum scan, there is no need for a postpartum 
scan for the purpose of the study. 
 
2) If no surgery performed - subjective assessment of the ultrasound image by the ultrasound 
examiner at postpartum scan: 
 
The subjective assessment of the mass will include: 
 
- 
A: Benign or Malignant (borderline or invasive) 

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- 
B: Probability of malignancy (level of certainty / confidence with the diagnosis as being 
benign or malignant and managing it as that): 
1 = benign 
2 = probably benign 
3 = uncertain/not possible to classify 
4 = probably malignant (borderline / invasive) 
5  = malignant (borderline / invasive); 
- 
C: Self impression: presumed histological diagnosis (e.g. dermoid, serous cystadenoma, 
endometrioma, decidualised endometrioma, abscess…); 
- 
D: Management: conservative management with ultrasound follow-up, surgery by 
general gynaecologist, surgery by oncological surgeon, other. 
 
The final outcome is defined as described below 
 
• 
Ovary normal at postpartum scan, then outcome = benign 
• 
Not operated on and level of certainty/confidence at postpartum scan = 1-2, then 
outcome = benign 
• 
Not operated on and level of certainty/confidence at postpartum scan = 5, then 
outcome = malignant 
• 
Not operated on and level of certainty/confidence at postpartum scan = 3-4, then 
outcome = uncertain 
• 
Operated and histology = benign, then outcome = benign (even if surgery > 120 days 
after postpartum scan) 
• 
Operated within 120 days since postpartum scan and histology = malignant, then 
outcome = malignant 
• 
Operated > 120 days since postpartum scan AND histology = malignant AND level of 
certainty/confidence at postpartum scan is 4-5, then outcome = malignant 
• 
Operated > 120 days since postpartum scan AND histology = malignant AND level of 
certainty/confidence at postpartum scan is 1-3, then outcome = uncertain 
• 
Neither surgery nor postpartum scan (within 0-90 days) performed, then outcome = 
uncertain. 
 
Additional information 
 
At every scan, irrespective of gestation or which arm of the study the patient falls under, the 
following are recorded in this specific order:  
 
1) Subjective assessment (A-D as described above) and the following additional E-G criteria: 
- 
E: Any subjective ultrasound change to adnexal mass from previous scan (five options): 1) 
yes, change noted; 2) no change noted; 3) adnexal mass no longer detectable (no ovary seen); 4) 
adnexal mass no longer detectable with only a normal ovary seen; 5) unsure (comment to 
explain why). 
- 
F: Colour score of ovarian mass: score 1, 2, 3, 4 

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- 
G: If papillations present: 1) number of papillations; 2) three orthogonal diameters of 
largest papillary projection i.e. height, base 1 and base 2; 3) smooth rounded papillations - yes / 
no; 4) colour in papillation - score 1, 2, 3, 4 (choose worst case scenario in case of multiple 
papillations). 
 
2) Modified Benign Descriptors and ADNEX model variables. 
 
Modified Benign Simple Descriptors and ADNEX model variables will be recorded for all 
arms of the study but will not be used when deciding on management (Appendix 1). 
 
Images of all four descriptors variables are shown and selected by ticking. The ultrasound 
ADNEX model variables are listed and filled in as per IOTA website and application. To 
ensure minimum inference, they will be recorded on a separate page from the subjective 
assessment on the computer software programme (Clinical Data Miner, CDM). 
 
Modified Benign Descriptors and ADNEX model will not be used to guide management - only 
subjective assessment of the expert scanner. Therefore, participating ultrasound examiners 
are asked NOT to calculate the risk of malignancy using ADNEX, because the management 
decision should not be influenced by the results of ADNEX. 
 
CA125 must be measured at the 11-14 week scan and at the inclusion scan if done before 11 
weeks OR after 14 weeks. It should be done within two weeks (+/- two weeks) of the scan - 
this must be prior to surgery, if surgery has been arranged. 
 
If found to be pregnant again at the 0-90 days postpartum scan, the outcome will be 
recorded in the same manner as described above. The patient can be recruited again as a 
separate case, but only if the patient has presented with a new cyst. 
 
Retrospectively from the notes and patient’s history, complications such as torsion and rupture 
that may have occurred will also be recorded. 
 
6.3 Definition of level of ultrasound experience   
 
The level of ultrasound experience is based on the number of gynaecological scans in non-
pregnant women that the examiner has performed at the start of the study. Basic experience is 
defined as <500 scans, intermediate experience as 500-5000 scans, and expert experience as 
>5000. In addition, we also record other information related to experience: the EFSUMB 
classification47 and the number of ovarian masses that the examiner has examined with 
ultrasound during the past year (classified as <50 (< 1 per week); 50-200 (up to 4 per week); 
>200 (> 4 per week)). 
 
Only those patients where the management decision was made based on the findings of an 
expert ultrasound examiner will be included in the study. The management decision itself need 
not be made by the expert ultrasound examiner. 
 

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We advise that all scans are done by the same ultrasound examiner. If not possible, as a 
minimum, the images from all scans of the same patient should be assessed by the same 
ultrasound examiner. 
 
6.4 Surgical intervention 
 
Surgery will be performed according to local protocols and the lead clinician for the patient. The 
reason for surgery, for example, symptoms, suspected torsion or cyst rupture or concern for 
malignant potential, will be recorded as part of the study. The tumour should be removed as per 
clinical practice. All histology will be reported and collected as per clinical practice and histology 
results will be documented for the study (Appendix 5).  
 
6.5 Study Closure 
 
We aim to recruit approximately 855 pregnant patients from 19 tertiary referral centres, with a 
minimum study duration of three years (please refer to section 7). 
 
6.6 Documentation and Communication 
 
Clinical data, patient demographics and ultrasound findings will be recorded prospectively in a 
computer software programme, acting as a web-based database (Clinical Data Miner, CDM - 
Appendices 2-5). This is a secured data collection software, dedicated for p-IOTA downloaded 
on password secured hospital computers. Data after entry are locked and cannot be changed.  
 
The flow will be as follows: patient history, initial ultrasound scan, follow-up ultrasound scans, 
mass complications during pregnancy and surgical findings if applicable.  
 
General procedures 
 
Upon inclusion in the study, written informed consent is obtained from the patient. First, clinical 
information about the patient is entered into CDM, including information related to gestational 
age at time of scan and whether the mass was known before pregnancy. Second, the ultrasound 
examiner provides a diagnosis based on subjective assessment and enters the Modified Benign 
Simple Descriptors and ADNEX model variables directly after. The Modified Benign Simple 
descriptors and the ADNEX models are not used to decide on management. 
 
Clinical Information 
 
As the type of centre (oncological vs non-oncological centre) is a predictive variable in the 
ADNEX model, this information will be filled in. An oncological centre is a tertiary referral 
centre with a specific gynaecological oncology unit. 
 
The ultrasound system used, ultrasound modality (transabdominal and/or transvaginal) and 
the name of the ultrasound examiner will be recorded. All ultrasound examiners must have 
passed the IOTA certification test.  
 

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Appendix 2 outlines the specific general patient characteristics which will be recorded at the 
inclusion scan. 
 
CA125 will be analysed and recorded at the inclusion scan and at the 11-14 week scan but must 
not be used to guide clinical management. 
 
Ultrasound examination 
 
We recognise that most patients will present with a solitary mass. However, a minority will 
have more than one on one ovary or bilaterally. Therefore, only the most suspicious non-
physiological adnexal mass or physiological cyst (if the largest diameter measures 5cm or more) 
should be included. The chosen mass should have a unique identifier in the form of a numeral 
(1,2,3..) with letter ‘L’ or ‘R’ to signify side (for example, 1L or 2R) should be given to the mass 
so that it can be identified throughout pregnancy and hence avoid errors. That label should also 
be written on the ultrasound image so as not to confuse masses in the same ovary with each 
other at follow-up scans. In case of two similar masses, the one with the largest dimension or 
most easily accessible with ultrasound should be selected for inclusion.  
 
A standardised transvaginal (supplemented with transabdominal if transvaginal is not 
sufficient) examination is performed. When a colour Doppler ultrasound examination is 
performed, the pulse repetition frequency should be 0.3-0.6 KHz. The colour Doppler gain 
should be increased until colour Doppler artefacts appear and then lowered until just below the 
reappearance of colour Doppler artefacts. Ultrasound frequency and “priority” (grey scale or 
colour/Power Doppler) must also be optimised when using colour/power Doppler. Doppler 
ultrasound should be used with all masses included, irrespective of gestational age. 
 
Collection of ultrasound images and ultrasound volumes 
 
All participants will be asked to store a sufficient number of high-quality transvaginal 
ultrasound images/volumes of all masses. Images must be stored if they are suggestive of a 
malignancy, decidualisation and masses with papillary projections. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7. STUDY OUTCOME MEASURES 
 
7.1 Primary Outcome Measures 
 
- 
Estimation of the false discovery rate when the ADNEX Model is applied at 11-14 weeks. 
 
7.2 Secondary Outcome Measures 
 
- 
Estimation of the false discovery rate when the 2-step strategy (i.e. Modified Benign 
Simple Descriptors followed by ADNEX) is applied at 11-14 weeks. 
- 
Estimation of the false discovery rate when the ADNEX Model and the 2-step strategy (i.e. 
Modified Benign Simple Descriptors followed by ADNEX) are applied at any time point during 
pregnancy; 
- 
Estimation of the ability of the ADNEX model and of the 2-step strategy (sensitivity, 
specificity, C-index, calibration intercept, calibration slope, clinical utility) to discriminate 
between benign and malignant adnexal masses at 11-14 weeks gestation. 
- 
Estimation of the ability of the ADNEX model and the 2-step strategy (sensitivity, 
specificity, C-index, calibration intercept, calibration slope, clinical utility) to discriminate 
between benign and malignant adnexal masses when detected at any time point in pregnancy; 
- 
Evaluation of change in morphology of ovarian masses throughout pregnancy based on 
subjective assessment; 
- 
Evaluation of change throughout pregnancy and postpartum in number, size, colour score, 
and morphology of papillations based on subjective assessment. 
 
7.3 Tertiary Outcome Measures 
 
- 
Change in the ultrasound appearance of endometriomas during gestation; 
- 
Occurrence of complications such as rupture, torsion, or malignancy during pregnancy in 
patients with conservatively treated masses (cumulative incidence illustrated by ’reverse’ 
Kaplan-Meier curves). 
- 
Comparison of the performance of ADNEX with CA125 and that of ADNEX without CA125. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. STUDY POPULATION AND SAMPLE SIZE 
 
In an ideal scenario, the results of this study will point to a very low false positive rate when 
applying ADNEX and Modified Benign Simple Descriptors to masses in pregnancy. Ideally, all 
participating centres should have been ‘tried and tested’ by IOTA already to minimize issues 
with data collection and missing data.  
 
Our sample population will come from Early Pregnancy Units and from Tertiary referral centres 
for ultrasound with or without an oncology department attached to it. The sample size 
estimation is based on data from Tertiary referral centres.  
 
The table below gives the sensitivity, specificity, and false discovery rate (defined as 1 minus 
positive predictive value) based on ADNEX thresholds as estimated in surgically and 
conservatively managed masses in the IOTA 5 study (non-pregnant patients).43 It assumes a 
prevalence of malignancy in pregnant women presenting in tertiary referral centers of 8% 
(based on a survey of a number of IOTA recognized centers; unpublished data). At a risk 
threshold of 10% (risk of malignancy calculated by ADNEX), the false discovery rate may be too 
high (65%) because of the low prevalence of malignancy in pregnant women. A risk threshold of 
25% to 40% (Dutch standard in non-pregnant women) appears to offer a good balance between 
sensitivity (detection of malignant masses) and false discovery rates (false positive results may 
lead to intervention during pregnancy in benign masses). 
 
threshold 
 
sensitivity 
speci
ficity 
false discovery rate 
(risk of malignancy 
according to ADNEX)  
100*(number classified as 
cancer/number of cancer) 
100*(number 
benign/number classified 
as cancer) 
1 
 
99.1 
12.0 
91.1 
3 
 
94.7 
59.7 
83.0 
5 
 
93.3 
76.4 
74.4 
10 
 
91.2 
85.3 
65.0 
15 
 
87.3 
89.0 
59.2 
20 
 
83.5 
91.5 
53.9 
25 
 
80.2 
93.1 
49.7 
30 
 
77.3 
94.4 
45.4 
40 
 
73.0 
95.8 
39.8 
50 
 
66.7 
97.1 
33.3 
 
 
The table below assumed an average of 15 pregnant women per year per tertiary referral center 
and assumed a sensitivity of 73% and a specificity of 95.8%. With 19 centers included in the 
data collection, the expected total sample size in three years is 855 pregnant women and 68 
malignancies. This allows us to estimate the specificity, sensitivity, and false discovery rate with 
a precision (width 95% CI/2) of 1%, 11% and 11%, respectively.  
 
 
 

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Number 
of 
centers 
n 
n 
malignancy 
True 
+ve 
False 
-ve 
True 
-ve 
False 
+ve 
Precision 
sensitivity 
Precision 
false 
discovery 
rate 
Precision 
specificity 
20 
900 
72 
53 
19 
793 
35 
11% 
11% 
1% 
19 
855 
68.4 
50 
18 
754 
33 
11% 
11% 
1% 
18 
810 
64.8 
47 
17 
714 
31 
11% 
11% 
2% 
17 
765 
61.2 
45 
17 
674 
30 
12% 
12% 
2% 
16 
720 
57.6 
42 
16 
635 
28 
12% 
12% 
2% 
15 
675 
54 
39 
15 
595 
26 
12% 
12% 
2% 
14 
630 
50.4 
37 
14 
555 
24 
13% 
13% 
2% 
13 
585 
46.8 
34 
13 
516 
23 
13% 
13% 
2% 
12 
540 
43.2 
32 
12 
476 
21 
14% 
14% 
2% 
11 
495 
39.6 
29 
11 
436 
19 
15% 
14% 
2% 
10 
450 
36 
26 
10 
397 
17 
15% 
15% 
2% 
9 
405 
32.4 
24 
9 
357 
16 
16% 
16% 
2% 
8 
360 
28.8 
21 
8 
317 
14 
17% 
17% 
2% 
7 
315 
25.2 
18 
7 
278 
12 
18% 
18% 
2% 
6 
270 
21.6 
16 
6 
238 
10 
20% 
20% 
3% 
5 
225 
18 
13 
5 
198 
9 
22% 
21% 
3% 
4 
180 
14.4 
11 
4 
159 
7 
24% 
24% 
3% 
3 
135 
10.8 
8 
3 
119 
5 
28% 
27% 
4% 
2 
90 
7.2 
5 
2 
79 
3 
33% 
33% 
5% 
1 
45 
3.6 
3 
1 
40 
2 
42% 
42% 
8% 
 
The table below repeats the same calculation, now assuming sensitivity of 80.2% and specificity 
of 93.1%. Including 19 centers allows us to estimate the specificity, sensitivity, and false positive 
rate with a precision (width 95% CI/2) of 2%, 11% and 10%, respectively.  
 
Centre 
Number 
n 
n 
malignancy 
True 
+ve 
False 
-ve 
True 
-ve 
False 
+ve 
Precision 
sensitivity 
Precision 
false 
discovery 
rate 
Precision 
specificity 
20 
900 
72 
58 
14 
771 
57 
11% 
10% 
2% 
19 
855 
68.4 
55 
14 
732 
54 
11% 
10% 
2% 
18 
810 
64.8 
52 
13 
694 
51 
11% 
10% 
2% 
17 
765 
61.2 
49 
12 
655 
49 
12% 
11% 
2% 
16 
720 
57.6 
46 
11 
617 
46 
12% 
11% 
2% 
15 
675 
54 
43 
11 
578 
43 
12% 
11% 
2% 
14 
630 
50.4 
40 
10 
540 
40 
13% 
12% 
2% 
13 
585 
46.8 
38 
9 
501 
37 
13% 
12% 
2% 
12 
540 
43.2 
35 
9 
463 
34 
14% 
13% 
2% 
11 
495 
39.6 
32 
8 
424 
31 
15% 
13% 
2% 
10 
450 
36 
29 
7 
385 
29 
15% 
14% 
3% 
9 
405 
32.4 
26 
6 
347 
26 
16% 
15% 
3% 
8 
360 
28.8 
23 
6 
308 
23 
17% 
15% 
3% 
7 
315 
25.2 
20 
5 
270 
20 
18% 
17% 
3% 

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6 
270 
21.6 
17 
4 
231 
17 
20% 
18% 
3% 
5 
225 
18 
14 
4 
193 
14 
22% 
20% 
4% 
4 
180 
14.4 
12 
3 
154 
11 
24% 
22% 
4% 
3 
135 
10.8 
9 
2 
116 
9 
28% 
25% 
5% 
2 
90 
7.2 
6 
1 
77 
6 
33% 
30% 
6% 
1 
45 
3.6 
3 
1 
39 
3 
42% 
39% 
9% 
 
In addition, below are the minimum required sample sizes to demonstrate that IOTA-ADNEX 
has clinical utility in pregnant women at a range of thresholds for the IOTA-ADNEX model.48  
 
Threshold 
Assumed 
Standardized 
Net Benefit 
Assumed sNB 
treat all 
sNB 
treat none 
Target precision 
sNB 
(width 95% CI/2) 
N required 
(pregnant patients 
with eligible mass) 
5% 
0.790 
0.395 
0 
0.395 
28 
25% 
0.538 
<0 
0 
0.518 
57 
40% 
0.408 
<0 
0 
0.388 
165 
50% 
0.334 
<0 
0 
0.314 
325 
 
With a sample size of 855 patients and assuming a C-statistic of 0.90, we can calculate the C-
statistic with a precision (width of CI/2) of 0.04.48 With respect to calibration, with 855 patients 
we have enough data to detect if 54 cancers were predicted instead of 68 observed (O/E=1.26), 
and to detect if 86 cancers predicted instead of the 68 observed (O/E=0.80). We do note that the 
sample size is insufficient to detect an O/E of 1.10 or an O/E of 0.90. To detect miscalibration-in-
the-large of this magnitude would require 4389 patients.  
 
We conclude that with 855 patients, this study will be sufficiently powered to obtain an 
estimate of the primary outcome, the false discovery rate of ADNEX at a risk threshold of 40%, 
with a precision of 11%. The study is also sufficiently powered to study the following secondary 
outcomes with sufficient precision: diagnostic accuracy (sensitivity and specificity), the C-
statistic, and clinical utility (quantified by the Net Benefit) of ADNEX. The study is powered to 
detect moderate to large differences between (average) predicted and (average) observed risks, 
but underpowered to detect minor miscalibration. 
 
Moreover, we will validate the IOTA-ADNEX model at 10%, 25%, 40%, and 50% risk thresholds. 
Intervening when the risk of malignancy is 10% or higher is a very sensitive approach with few 
missed malignancies, but may lead to too many unnecessary interventions during pregnancy. In 
contrast, intervening when the risk of malignancy is 50% or higher will yield a much more 
specific approach, with fewer interventions during pregnancy, but may lead to more missed 
cancers 
 
Finally, data from adnexal masses encountered in two early pregnancy units will be collected 
and analysed separately to examine the distribution of predicted risks of malignancy and 
referral rates to tertiary care if ADNEX were used for triage (referral based on clinical decision 
at early pregnancy unit). In a period of three years and with an expected 5000 deliveries per 
center per year, we expect 30,000 pregnant women. With an expected prevalence of adnexal 
masses of 6%, we expect data on 1800 masses and at a BOT rate of 3-5% when an adnexal mass 
is picked up in pregnancy, between 50-90 malignancies (i.e. BOTs and invasive). 

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8.1 Summary 
 
Validation of diagnostic models will occur in subgroups according to type of center (referral center 
v. early pregnancy unit), as the prevalence of malignancy will likely influence performance of IOTA-
ADNEX and the Modified Benign Simple Descriptors. 
 
Validation of diagnostic models refers to: 
 
1) prospective validation of the false discovery rate of IOTA ADNEX and the two-step strategy at 
11-14 weeks GA (False Discovery Rate in this context is how many pregnancies with a benign mass 
would be referred to tertiary care); 
 
2) prospective validation of IOTA ADNEX and the two-step strategy in terms of 
sensitivity/specificity/c-index/calibration/net benefit at 11-14 weeks GA; 
 
3) prospectively validation of IOTA ADNEX and the two-step strategy to discriminate between 
benign and malignant adnexal masses when detected at any point during pregnancy, in terms of 
false discovery rate/sensitivity/specificity/c-index/calibration/net benefit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9. STUDY SUPERVISION AND MONITORING 
 
This study does not involve any risk to the participants. 
 
Central supervision: The IOTA Steering Committee is responsible for the protocol, quality 
control, advice on progress and final analysis and reporting of the study. 
 
The study will be co-ordinated by Dr Srdjan Saso, to ensure timely progress and regular 
participation. 
 
Local supervision: Principal Investigators are responsible for the data collection at their centres 
and communication with Dr Srdjan Saso. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10. REGULATORY ISSUES 
 
PUBLICATION POLICY 
The IOTA steering committee is responsible for publication of the data in scientific journals and 
will be listed as co-authors if they fulfil the requirements of authorship of the International 
Committee of Medical Journal Editors and in accordance with the requirements of the respective 
medical journal. 
 
The chief statistician is responsible for data analysis, contributes to study design (protocol draft) 
and will be listed as a co-author. Principal Investigators are also co-authors, according to the 
number of patients they contributed to the study (depending on the journal’s restriction of the 
number of co-authors) on condition that they contribute to writing the papers, read and 
approve the final version, and agree to be accountable for all aspects of the work, as defined by 
the International Committee of Medical Journal Editors and in accordance with the 
requirements of the respective medical journal. 
 
INTELLECTUAL PROPERTY 
The KU Leuven VAT number BE 419.052.173, represented by its department K.U. LEUVEN 
RESEARCH & DEVELOPMENT, having its office in 3000 Leuven, Waaistraat 6, Belgium, and 
represented by its university hospital, UNIVERSITAIRE ZIEKENHUIZEN LEUVEN holds all 
intellectual property rights that might result from the IOTA project (including, amongst others, 
this p-IOTA). Each participating centre shall remain the owner of its source data and may utilise 
such data AFTER the main scientific papers of the multicentre study have been published. 2D 
ultrasound images, clips and 3D ultrasound volumes may be used for educational purposes 
outside the study, as well as in other studies.  
 
ETHICS AND REGULATORY APPROVALS 
The multicentre project is first approved by the central Ethics Committee of UZ Leuven, Belgium 
and afterwards approved by the Ethics Committee in each investigating centre. The study will 
be performed in accordance with the terms of the protocol, generally accepted standards of 
Good Clinical Practice and the investigators will adhere to all applicable laws and regulations 
governing the conduct of clinical trials, including but not limited to the ICH Harmonised 
Tripartite Guidelines for Good Clinical Practice and the Declaration of Helsinki.  
 
Each Participating centre shall obtain an informed consent (oral or written, depending on the 
applicable local legislation and local Ethics Committee requirements) for all patients prior to 
their enrolment and participation in the Study in compliance with all applicable laws, 
regulations and the approval of the (local) Ethics Committee.  
 
The Investigator shall treat all information and data relating to the Study as confidential and 
shall not disclose such information to any third parties or use such information for any purpose 
other than the performance of the Study. The collection, processing and disclosure of encoded 
personal data, such as patient health and medical information is subject to compliance with 
applicable personal data protection and the processing of personal data and/or the privacy laws 
applicable to the Participating centre’s location). 
 
 

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Sponsor is subject to the rights and obligations as ‘data controller’ set forth under the 
European Data Protection Directive (95/46/EC) (and upon its entry into force the General Data 
Protection Regulation 2016/679 (“GDPR”)) in relation to the processing of Personal Data.  
Each participating centre is subject to the rights and obligations as ‘data processor’ set forth 
under the European Data Protection Directive (95/46/EC) (and upon its entry into force the 
GDPR)  in relation to the processing of Personal Data. 
Parties’ rights and obligations with respect to Personal Data (as defined in Appendix 6) are 
further detailed in Appendix 6. 
 
INSURANCE 
Each participating centre is fully responsible for patient care within its own hospital in 
agreement with local laws. Each centre is also responsible for all legal aspects of patient care 
and for its own insurance for all matters related to this study as required by local laws. 
 
For Belgian participating centres 
Art. 29 of the Belgian Law relating to experiments on human persons dated May 7th, 2004 
applies. Prior to the start of the study, the Sponsor shall enter into an insurance contract in 
order to adequately cover study participants from Belgian sites in accordance with art. 29 of the 
said law. 
For non-Belgian participating Sites 
Each Participating centre shall have and maintain in full force and effect during the term of this 
study (and for a reasonable period following termination of the study, adequate insurance 
coverage for other possible damages resulting from the study at the participating centre, as 
required by local law. Each such insurance coverage shall be in amounts appropriate to the 
conduct of the services of the participating centre under this study. The participating centre and 
Sponsor shall be solely responsible for any deductible or self-insured retention under any such 
policies.  
 
 
FINANCIAL ASPECTS 
Gynaecological ultrasound and clinical evaluations as well as treatment and pathological 
diagnosis are performed in the framework of routine clinical practice and require no additional 
expenses. There is no financial compensation for patients, including the postpartum scan, which 
is standard clinical practice. 
 
 

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11. REFERENCES 
 
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6. Leiserowitz G, Xing G, Cress R, Brahmbhatta B, Dalrymple J, Smith L. Adnexal masses in 
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8. Alcázar JL, Pascual MA, Graupera B, Aubá M, Errasti T, Olartecoechea B, Ruiz-Zambrana 
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9. Sayasneh A, Kaijser J, Preisler J, Johnson S, Stalder C, Husicka R, Guha S, Naji O, Abdallah 
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Timmerman D, Bourne T. A multicenter prospective external validation of the diagnostic 
performance of IOTA simple descriptors and rules to characterize ovarian masses. 
Gynecol Oncol. 2013; 130:140-6. 
10. Sayasneh A, Ferrara L, De Cock B, Saso S, Al-Memar M, Johnson S, Kaijser J, Carvalho J, 
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T. Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a 
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11. Timmerman D, Testa AC, Bourne T, Ferrazzi E, Ameye L, Konstantinovic ML, Van Calster B, 
Collins WP, Vergote I, Van Huffel S, Valentin L. Logistic regression model to distinguish 
between the benign and malignant adnexal mass before surgery: a multicentre study by the 
International Ovarian Tumour Analysis Group. J Clin Oncol. 2005; 23:8794-8801 
12. Timmerman D, Van Calster B, Testa AC, Guerriero S, Fischerova D, Lissoni AA, Van Holsbeke 
C, Fruscio R, Czekierdowski A, Jurkovic D, Savelli L, Vergote I, Bourne T, Van Huffel S, 

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Valentin L. Ovarian cancer prediction in adnexal masses using ultrasound based logistic 
regression models: a temporal and external validation study by the IOTA group. Ultrasound 
Obstet Gynecol. 2010; 36:226-34. 
13. Timmerman D, Ameye L, Fischerova D, Epstein E, Melis GB, Guerriero S, Van Holsbeke C, 
Savelli L, Fruscio R, Lissoni AA, Testa AC, Veldman J, Vergote I, Van Huffel S, Bourne T, 
Valentin L. Simple ultrasound rules to distinguish between benign and malignant adnexal 
masses before surgery: prospective validation by IOTA group. BMJ. 2010; 341: c6839-
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14. Timmerman D, Van Calster B, Testa A, Savelli L, Fischerova D, Froyman W, Wynants L, Van 
Holsbeke C, Epstein E, Franchi D, Kaijser, Czekierdowski, Guerriero, Fruscio R, Leone F, 
Rossi A, Landolfo C, Vergote I, Bourne T, Valentin L.  Predicting the risk of malignancy in 
adnexal masses based on the Simple Rules from the International Ovarian Tumour 
Analysis group. Am J Obstet Gynecol. 2016; 214: 424-437 
15. Van Calster B, Van Hoorde K, Valentin L, Testa AC, Fischerova D, Van Holsbeke C, Savelli 
L, Franchi D, Epstein E, Kaijser J, Van Belle V, Czekierdowski A, Guerriero S, Fruscio R, 
Lanzani C, Scala F, Bourne T, Timmerman D; International Ovarian Tumour Analysis 
Group. Evaluating the risk of ovarian cancer before surgery using the ADNEX model to 
differentiate between benign, borderline, early and advanced stage invasive, and 
secondary metastatic tumours: prospective multicentre diagnostic study. BMJ. 2014; 15; 
349: g5920. 
16. Timmerman D, Testa AC, Bourne T, Ameye L, Jurkovic D, Van Holsbeke C, Paladini D, Van 
Calster B, Vergote I, Van Huffel S, Valentin L. Simple ultrasound-based rules for the 
diagnosis of ovarian cancer. Ultrasound Obstet Gynecol. 2008; 31: 681-90 
17. Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy 
index incorporating CA 125, ultrasound and menopausal status for the accurate 
preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990; 97:922–9 
18. Davies AP, Jacobs I, Woolas R, Fish A, Oram D. The adnexal mass: benign or malignant? 
Evaluation of a risk of malignancy index Br J Obstet Gynaecol. 1993; 100:927–31. 
19. Timmerman D, Van Calster B, Jurkovic D, Valentin L, Testa AC, Bernard JP, Van Holsbeke 
C, Van Huffel S, Vergote I, Bourne T. Inclusion of CA-125 does not improve mathematical 
models developed to distinguish between benign and malignant adnexal tumors. J Clin 
Oncol. 2007; 25:4194-200.  
20. Van Calster B, Timmerman D, Bourne T, Testa AC, Van Holsbeke C, Domali E, Jurkovic D, 
Neven P, Van Huffel S, Valentin L. Discrimination between benign and malignant adnexal 
masses by specialist ultrasound examination versus serum CA-125. J Natl Cancer Inst. 
2007; 99:1706-14.  
21. Nustad K, Bast RC Jr, Brien TJ, Nilsson O, Seguin P, Suresh MR, Saga T, Nozawa S, Bormer 
OP, de Bruijn HW, Nap M, Vitali A, Gadnell M, Clark J, Shigemasa K, Karlsson B, Kreutz FT, 
Jette D, Sakahara H, Endo K, Paus E, Warren D, Hammarstrom S, Kenemans P, Hilgers 
J: Specificity and affinity of 26 monoclonal antibodies against the CA 125 antigen: first 
report from the ISOBM TD-1 workshop. International Society for Oncodevelopmental 
Biology and Medicine. Tumour Biol. 1996, 17: 196–219.  
22. Sarandakou A, Protonotariou E, Rizos D. Tumor Markers in Biological Fluids Associated 
With Pregnancy. Crit Rev Cl Lab Sci. 2007; 44:2, 151-178 
23. Yazbek J, Salim R, Woelfer B, Aslam N, Lee CT, Jurkovic D. The value of ultrasound 
visualization of the ovaries during the routine 11-14 weeks nuchal translucency scan. 
Eur J Obstet Gynecol Reprod Biol. 2007; 132:154-8.  

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24. Mukhopadhyay A, Shinde A, Naik R. Ovarian cysts and cancer in pregnancy. Best Pract 
Res Clin Obstet Gynaecol. 2016; 33:58-72. 
25. Akazawa M, Onjo S. Malignant Transformation of Mature Cystic Teratoma: Is Squamous 
Cell Carcinoma Different From the Other Types of Neoplasm? Int J Gynecol Cancer. 2018; 
28: 1650-1656. 
26. Ayhan A, Aksu T, Develioglu O, Tuncer ZS, Ayhan A. Complications and bilaterality of 
mature ovarian teratomas (clinicopathological evaluation of 286 cases). Aust N Z J 
Obstet Gynaecol. 1991; 31:83-85. 
27. Caspi B, Levi R, Appelman Z, Rabinerson D, Goldman G, Hagay Z. Conservative 
management of ovarian cystic teratoma during pregnancy and labor. Am J Obstet 
Gynecol. 2000; 182:503-5.  
28. Hoo W, Yazbek J, Hollan T, Mavrelos D, Tong E, Jurkovic D. Expectant management of 
ultrasonically diagnosed ovarian dermoid cysts: is it possible to predict outcome? 
Ultrasound Obstet Gynecol. 2010; 36:235-40 
29. Caspi B, Appelman Z, Rabinerson D, Zalel Y, Tulandi T, Shoham Z. The growth pattern of 
ovarian dermoid cysts: a prospective study in pre-menopausal and postmenopausal 
women. Fertil Steril; 68:501–505. 
30. Morice P. Borderline tumours of the ovary and fertility. Eur J Cancer 2006; 42: 149-158.  
31. Hoover K, Jenkins T. Evaluation and management of adnexal mass in pregnancy. Am J 
Obstet Gynecol. 2011; 205:97-102 
32. Fauvet R, Brzakowski M, Morice P, Resch, B, Marret H, Graesslin O, Daraı E.  Borderline 
ovarian tumours diagnosed during pregnancy exhibit a high incidence of aggressive 
features: results of a French multicentre study. Annals of Oncology. 2012; 23:1481–
1487.  
33. Poder L, Coakley FV, Rabban JT, Goldstein RB, Aziz S, Chen LM. Decidualized 
endometrioma during pregnancy: recognizing an imaging mimic of ovarian 
malignancy. J Comput Assist Tomogr. 2008; 32:555–558. 
34. Condous G, Khalid A, Okaro E, Bourne T: Should we be examining the ovaries in 
pregnancy? Prevalence and natural history of adnexal pathology detected at first-
trimester sonography. Ultrasound Obstet Gynecol. 2004; 24:62–66.  
35. Pateman K, Moro F, Mavrelos D, Foo X, Wee-Liak H Hoo, Jurkovic D. Natural history of 
ovarian endometrioma in pregnancy. BMC Womens health. 2014; 14:128.  
36. Mascilini F, Savelli L, Scifo M, Exacoustos C, Timor-Tritsch I, De Blasis I, Moruzzi M, 
Pasciuto T, Scambia G, Valentin L, Testa A. Ovarian masses with papillary projections 
diagnosed and removed during pregnancy: ultrasound features and histological 
diagnosis. Obstet Gynecol. 2017; 50:116-123 
37. Moro F, Mascilini F, Pasciuto T, Leombroni M, Li Destri M, De Blasis I, Garofalo S, 
Scambia G, Testa AC. Ultrasound features and clinical outcome of patients with 
malignant ovarian masses diagnosed during pregnancy: experience of a gynecological 
oncology ultrasound centre. Int J Gynecol Cancer. 2019; 29:1182-1194. 
38. Testa AC, Mascilini F, Quagliozzi L, Moro F, Bolomini G, Mirandola MT, Moruzzi MC, 
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Comparison of adnexal torsion between pregnant and nonpregnant women. Am J Obstet 
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40. Ginath S, Shalev A, Keidar R, Kerner R, Condrea A, Golan A, Sagiv R. Differences between 
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41. Bignardi T, Condous D. The management of ovarian pathology in pregnancy.  Best Pract 
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42. Yen CF, Lin SL, Murk W, Wang CJ, Lee CL, Soong YK, Arici A.  Risk analysis of torsion and 
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45. Balinskaite V, Bottle A, Sodhi V, Rivers A, Bennett PR, Brett SJ, Aylin P. The Risk of 
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 4251.  
 
 
 
 
 
 
 

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12. APPENDICES 
 
Appendix 1 - Ultrasound examination IOTA terms and definitions 
 
A standardised ultrasound examination following the IOTA protocol is carried out. All 
ultrasound variables are included in the dedicated software. In the database 0 always means NO 
and 1 always means YES. 
 
The adnexal lesion is that part of an ovary or of an adnexal mass that is judged by 
ultrasonography to be not consistent with normal physiology.  This can be a persistent 
unilocular cyst, surrounded by normal looking ovarian stroma with some follicles.  In this case 
the whole ovary containing the cyst is the ‘ovary’, whereas the unilocular cyst is the ‘lesion’.  
Both are measured and the cyst is described as being ‘unilocular’ and not ‘unilocular-solid’. In 
other cases the lesion is separate from the ovary (e.g. hydrosalpinx).  Again, both ovary and 
lesion are measured separately.  In other cases no normal ovarian stroma is seen.  In these cases 
the lesion and the ovary are undistinguishable and the measurement of lesion and ovary will be 
the same. 
 
Measurements (in mm): 
The ovary in two perpendicular planes 
The lesion in two perpendicular planes 
The volume of the tumour is calculated from the three diameters in two perpendicular planes by 
the software.  
 
• The presence of ascites (i.e. fluid outside the pouch of Douglas) is noted (yes/no). 
• Fluid in the pouch of Douglas is measured in the sagittal plane (the largest anteroposterior 
diameter is given). 
 
 
 
 
 
 
 
• An incomplete septum (as seen in hydrosalpinges) is defined as a thin strand of tissue 
running across the cyst cavity from one internal surface to the contralateral side, but is not 
complete in some scanning planes. If a cyst only has incomplete septa, it is unilocular, despite 
the fact that in certain sections the cyst appears to be multilocular. 
• Solid means echogenicity suggesting the presence of tissue (e.g. the myometrium, the ovarian 
stroma, myomas, fibromas).  Blood clots can be distinguished from solid tissue by looking for 
internal movement when gently pushing the structure with the transducer. The presence of 
blood flow (with the appropriate colour Doppler settings) is diagnostic for solid tissue. The 
absence of flow is not diagnostic. In cases of doubt the lesion should be classified as solid. 
• Solid papillary projections are defined as any solid projections into the cyst cavity from the 
cyst wall or septum greater than or equal to 3 mm in height 
 
 
Bas

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If it is uncertain whether a solid papillary projection or an incomplete septum is present, the 
‘worse case scenario’ is used.  For example, ‘cogwheel excrescences’ and ‘beads-on-a-string’ (as 
seen in hydrosalpinges) should be classified as papillary excrescences if their height is greater 
than or equal to 3 mm.  The ‘white ball’ in a dermoid (i.e. Rokitansky node) should not be 
classified as a solid papillary projection. 
 
The ‘sludge’ on the internal walls of endometriotic cysts is not regarded as a papillary projection. 
In these cases the internal walls are usually ‘irregular’. 
 
• The number of separate papillary projections is noted (1/2/3/more). 
• The presence of flow within some of these projections is noted (yes/no). 
• Solid papillary projections are described as being ‘smooth’ or ‘irregular’ (e.g. cauliflower-like 
- this variable will be added to CDM). 
 
In some cases, it is difficult to judge whether it is a papillary projection and from which point to 
measure the projection. In these cases ,it may be helpful to use an imaginary line as shown in 
the schematic drawing:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All lesions are qualitatively classified into one of five categories: 
 
 
 
Hei
 

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1.  unilocular (a unilocular cyst without septa and without solid parts or papillary 
structures).  Normal ovarian stroma is not regarded as a ‘solid component’ (e.g. a 
peritoneal cyst with one cyst locule, containing a normal ovary, is unilocular and not 
unilocular-solid). 
 
 
 
 
 
 
 
 
 
incomplete septum; e.g. in hydrosalpinx) 
 
 
2.  unilocular cyst with solid component, i.e. a unilocular solid cyst (a unilocular cyst with a 
measurable solid component or at least one papillary structure).  This category may 
include pyo- or hydrosalpinges with the so-called ‘beads-on-a-string’ or ‘cogwheel’ 
appearance if the solid protrusions are  3mm. 
 
 
 
 
 
 
 
 
 
 
 
 
3.  multilocular (a cyst with at least one septum but no measurable solid components or 
papillary projections). The ‘lesion’ is measured as indicated by the arrows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 

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4.  multilocular with solid component, multilocular solid tumour (a multilocular cyst with a 
measurable solid component or at least one papillary structure) 
 
 
 
 
 
 
 
 
5.  solid (a tumour where the solid components comprise 80% or more of the tumour when 
assessed in a two-dimensional section).  
 
 
 
 
 
 
 
 
    (solid tumour with an irregular internal cyst wall) 
 
A solid tumour may contain papillary projections protruding into cysts. 
 
Quantitative assessment of morphology 
 
• In cystic-solid tumours the largest solid component is measured separately (in three 
perpendicular planes).  The solid component is noted as being smooth or irregular (i.e. 
cauliflower-like).  In some cases a solid papillary projection is the largest solid component 
and thus the papillary projection is recorded both as papillary projection and as solid 
component. 
• The internal wall is also noted as being smooth or irregular.  
 
 
 
 
 
 
 
 
Smooth 
 
Smooth 
 
Irregular 
 
If there is a solid papillary projection, then the wall is irregular by definition. 
 
• The external walls of tumours are not described unless they the tumour is solid. 
 
 
 
 
 
 
 
 
 
 

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• In case of solid tumours the description of the internal wall being smooth or irregular is 
usually not applicable but the outline of the tumour is described as smooth or irregular.  
• If there is any irregularity in either the inner wall of any cyst or in the outer wall of a solid 
tumour or on the surface of a solid component, the lesion is described as ‘irregular’. 
• The dominant feature of the cystic contents is described as anechoic (black), low-level 
echogenic (homogeneous low level echogenic as seen in mucinous tumours), ‘ground glass’ 
appearance (homogeneously dispersed echogenic cystic contents, as often seen in 
endometriotic cysts), haemorrhagic (with internal thread-like structures, representing fibrin 
strands; it is possible to describe the echogenicity as star-shaped, cobweb-like or jelly-like) 
or mixed echogenic (as often seen in teratomas) (see images attached).  
 
 
 
 
 
 
 
 
 
Anechoic 
Low level 
Ground glass        Haemorrhagic     Haemorrhagic 
 
 
 
 
 
 
 
 
Mixed  
Mixed (old blood-fluid level  
 
         Mixed (e.g. abscess) 
 
 
 
or fat-fluid level) 
 
• The presence of acoustic shadows, defined as loss of acoustic echo behind a sound-absorbing 
structure, is noted.  Solid tumours are identified by the appearance of the internal texture, by 
the absence of internal movement when moving the transducer or by colour Doppler imaging 
(presence of central flow). 
• ‘Ovarian crescent sign’, defined as the presence of normal ovarian tissue adjacent to an 
adnexal tumour. 
• Ultrasound evidence of metastases (e.g. “omental cake” or peritoneal tumoural implants). 
(“absent” or “present”, mandatory new variable for phase 3 and 5) 
 
For quality control, at least one 2D greyscale and one 2D colour representative image, as well as 
3D volume must be saved. In addition, one greyscale and one colour representative video clip 
must also be saved.  Preferably, these should be stored digitally.  Photographs or video are 
acceptable as well. 
 
 
 
Modified Benign Simple Descriptors 
 
 
 
 
 
 
 
 
 
 
 
: : 
: :

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1. Unilocular cyst with ground-glass echogenicity in premenopausal woman with largest 
diameter < 10 cm  
2. Unilocular cyst with mixed echogenicity and acoustic shadows in pre-menopausual woman 
with largest diameter < 10 cm  
3. Unilocular anechoic cyst with smooth internal cyst walls and largest diameter < 10 cm  
4. All other unilocular cysts with smooth internal cyst walls and largest diameter < 10 cm  
 
ADNEX model 
 
ADNEX model15 includes three clinical predictors and six ultrasound predictors. The clinical 
predictors are: age (years), serum CA125 (U/mL) and type of centre to which the patient has 
been referred for ultrasound examination. Type of centre has been divided into oncology 
centres versus other centres. 
 
The ultrasound predictors are the maximal diameter of the lesion (mm), proportion of solid 
tissue (%), number of papillary projections (0, 1, 2, 3, > 3), presence of more than 10 cyst 
locules (yes/no), acoustic shadows (yes/no), and presence of ascites (yes/no). The proportion 
of solid tissue is defined as the ratio of the maximal diameter of the largest solid component and 
the maximal diameter of the lesion.  
 
 
 
 
 
 
 

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Appendix 2 - Data recorded at inclusion scan  
 
General information 
 
• 
Type of centre where scan performed: Tertiary Referral Centre / Oncology Centre with 
ultrasound attached / Early Pregnancy Unit  
• 
Patient referred from: self-referral, family doctor/GP, local/district hospital, Early 
Pregnancy Unit, obstetrics ultrasound department, private gynaecologist  
 
• 
Family history: 
Number of first-degree relatives with ovarian or breast cancer (0-20) 
 
• 
Medical history: 
 
 
 
Age (years)  
Previous oophorectomy (Yes/No); if yes, which side? (Right/Left) 
Is this pregnancy a result of fertility treatment? (Yes/No); Which type (in 
vitro 
fertilisation, 
intracytoplasmic 
sperm 
injection, 
intrauterine 
insemination)? 
 
• 
Adnexal mass-related (the index mass of this study): 
Diagnosed with this mass before pregnancy (Yes/No) 
If yes - how many months prior to today? 
 
Ultrasound data 
 
➢ Name of the ultrasound examiner 
➢ Date of scan 
➢ Gestational age according to ultrasound (Weeks….   Days….) 
 
➢ Ultrasound system used 
➢ Which modality used - transabdominal or transvaginal or transrectal 
➢ Ovarian or tubal or para-ovarian or uncertain? Left or right? 
 
Subjective assessment 
After ultrasonographic examination of the mass the investigator gives his/her subjective 
assessment of the mass: 
 
- 
A: Benign or Malignant (borderline / invasive); 
- 
B: Probability of malignancy (level of certainty / confidence with the diagnosis as being 
benign or malignant and managing it as that): 
1 = benign 
2 = probably benign 
3 = uncertain/not possible to classify 
4 = probably malignant (borderline / invasive) 
5  = malignant (borderline / invasive); 

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- 
C: Self impression: presumed histological diagnosis (e.g. functional cyst, haemorrhagic 
corpus luteum cyst, pregnancy-associated cyst, theca-lutein cyst, teratoma, serous cystadenoma, 
mucinous cystadenoma, serous cystadenofibroma, mucinous cystadenofibroma, fibroma, 
endometrioma, decidualised endometrioma, abscess, hydrosalpinx, invasive - specify type, 
borderline - specify type; granulosa cell tumour, dysgerminoma, other); 
- 
D: Management: conservative management with ultrasound follow-up, surgery by 
general gynaecologist, surgery by oncological surgeon, other; 
- 
E: (If mass diagnosed and scanned prior to pregnancy, proceed with question; otherwise 
non-applicable) Any subjective ultrasound change to adnexal mass from previous scan (five 
options): 1) yes, change noted; 2) no change noted; 3) adnexal mass no longer detectable (no 
ovary seen); 4) adnexal mass no longer detectable but replaced by a normal ovary; 5) unsure 
(comment to explain why). 
- 
F: Colour score of ovarian mass: score 1, 2, 3, 4 
- 
G: If papillations present: 1) number of papillations; 2) three orthogonal diameters (mm) 
of largest papillary projection i.e. height, base 1 and base 2; 3) smooth rounded papillations - 
yes / no; 4) colour in papillation - score 1, 2, 3, 4 (choose worst case scenario in case of multiple 
papillations). 
 
 
ADNEX Variables 
➢ Age 
➢ Oncology Centre (yes/no) 
➢ Maximum diameter of the lesion (mm) 
➢ Maximum diameter of largest solid component 
➢ Number of papillary projections (0, 1, 2, 3, > 3) 
➢ Presence of more than 10 cyst locules (yes/no) 
➢ Acoustic shadows (yes/no) 
➢ Presence of ascites (yes/no) 
➢ CA125 level (must be measured at 11-14 week scan and at the inclusion scan if done 
before 11 weeks OR after 14 weeks; it should be done within two weeks (+/- two 
weeks) of the scan - this must be prior to surgery, if surgery has been arranged) 
 
Modified Benign Simple Descriptors (tick images) 
1. Unilocular cyst with ground-glass echogenicity in premenopausal woman with largest 
diameter < 10 cm 
2. Unilocular cyst with mixed echogenicity and acoustic shadows in premenopausual woman 
with largest diameter < 10 cm 
3. Unilocular anechoic cyst with smooth internal cyst walls and largest diameter < 10 cm 
4. All other unilocular cysts with smooth internal cyst walls and largest diameter < 10 cm 
 
Ultrasound features suggestive of a complication of adnexal mass: no /yes 
- pop-up list (you can select more than one): 
o Suspected torsion 
o Infection/abscess 
o Haemorrhage 
o Rupture 
o Other, please specify:  …. 
 

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Management data 
 
• 
Suggested management: “What type of management do you propose for this patient 
based on ultrasound subjective assessment?” 
 
o Conservative management with one further ultrasound performed 0-90 days 
post-partum; 
o Conservative management with longitudinal follow-up as specified in the 
protocol (third arm of study - if patient consents to this); 
o Conservative management but with additional scans to the one listed in third 
arm of study with reason (pop-up: change in morphology, change in size, 
suspicion of malignancy; symptoms; other: specify); 
o Surgery by a gynaecologist or general surgeon; 
o Surgery by an oncological surgeon; 
o Other, specify 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3 - Data recorded at follow-up scan  
 
General information 
 
• 
Type of centre where scan performed: Tertiary Referral Centre / Oncology Centre with 
ultrasound attached / Early Pregnancy Unit  
 
Ultrasound data 
 
➢ Name of the ultrasound examiner 
➢ Date of scan 
➢ Gestational age according to ultrasound (Weeks….   Days….) 
 
➢ Ultrasound system used 
➢ Which modality used - transabdominal or transvaginal or transrectal 
➢ Mass detectable (yes/no; and if answer is ‘yes’) - pop-up: no ovary seen; ovary seen) 
➢ Ovarian or tubal or para-ovarian or uncertain? Left or right? 
 
Subjective assessment 
After ultrasonographic examination of the mass the investigator gives his/her subjective 
assessment of the mass: 
 
- 
A: Benign or Malignant (borderline or invasive) 
- 
B: Probability of malignancy (level of certainty / confidence with the diagnosis as being 
benign or malignant and managing it as that): 
1 = benign 
2 = probably benign 
3 = uncertain/not possible to classify 
4 = probably malignant (borderline / invasive) 
5 = malignant (borderline / invasive); 
- 
C: Self impression: presumed histological diagnosis (e.g. functional cyst, haemorrhagic 
corpus luteum cyst, pregnancy-associated cyst, theca-lutein cyst, teratoma, serous cystadenoma, 
mucinous cystadenoma, serous cystadenofibroma, mucinous cystadenofibroma, fibroma, 
endometrioma, decidualised endometrioma, abscess, hydrosalpinx, invasive - specify type, 
borderline - specify type; granulosa cell tumour, dysgerminoma, other); 
-  
D: Management: conservative management with ultrasound follow-up, surgery by 
general gynaecologist, surgery by oncological surgeon, other. 
- 
E: Any subjective ultrasound change to adnexal mass from previous scan (five options): 1) 
yes, change noted; 2) no change noted; 3) unsure (comment to explain why). 
- 
F: Colour score of ovarian mass: score 1, 2, 3, 4 
- 
G: If papillations present: 1) number of papillations; 2) three orthogonal diameters (mm) 
of largest papillary projection i.e. height, base 1 and base 2; 3) smooth rounded papillations - 
yes / no; 4) colour in papillation - score 1, 2, 3, 4 (choose worst case scenario in case of multiple 
papillations). 
 
 
 
 

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ADNEX Variables 
➢ Age 
➢ Oncology Centre (yes/no) 
➢ Maximum diameter of the lesion (mm) 
➢ Maximum diameter of largest solid component 
➢ Number of papillary projections (0, 1, 2, 3, > 3) 
➢ Presence of more than 10 cyst locules (yes/no) 
➢ Acoustic shadows (yes/no) 
➢ Presence of ascites (yes/no) 
➢ CA125 level (NOT TO BE MEASURED AT FOLLOW-UP SCANS) 
 
Modified Benign Simple Descriptors (tick images) 
1. Unilocular cyst with ground-glass echogenicity in premenopausal woman with largest 
diameter < 10 cm  
2. Unilocular cyst with mixed echogenicity and acoustic shadows in premenopausual woman 
with largest diameter < 10 cm  
3. Unilocular anechoic cyst with smooth internal cyst walls and largest diameter < 10 cm  
4. All other unilocular cysts with smooth internal cyst walls and largest diameter < 10 cm  
 
Ultrasound features suggestive of a complication of adnexal mass: no /yes 
- pop-up list (you can select more than one): 
o Suspected torsion 
o Infection/abscess 
o Haemorrhage 
o Rupture 
o Other, please specify:  …. 
 
Management data 
 
• 
Suggested management: “What type of management do you propose for this patient 
based on ultrasound subjective assessment?” 
 
o Conservative management with one further ultrasound performed 0-90 days 
post-partum; 
o Conservative management with longitudinal follow-up as specified in the 
protocol (third arm of study - if patient consents to this); 
o Conservative management but with additional scans to the one listed in third 
arm of study with reason (pop-up: change in morphology, change in size, 
suspicion of malignancy; symptoms; other: specify); 
o Surgery by a gynaecologist or general surgeon; 
o Surgery by an oncological surgeon; 
o Mass is no longer present and only a normal ovary is seen - end of follow-up and 
completion of study; 
o Other, specify. 
 
 
 

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Appendix 4 - Data recorded at 0-90 days postpartum scan 
 
General information 
• 
Type of centre where scan performed: Tertiary Referral Centre / Oncology Centre with 
ultrasound attached / Early Pregnancy Unit  
• 
Date of scan 
• 
Outcome of pregnancy: Live birth, stillbirth, miscarriage, ectopic 
• 
Date of delivery 
• 
In case of miscarriage - date when miscarriage was diagnosed 
• 
In case of an ectopic - date ectopic pregnancy was diagnosed 
 
• 
If ectopic or miscarriage – expectant, medical or surgical management? 
• 
Delivery mode: Spontaneous vaginal delivery, instrumental vaginal delivery, C/Section 
 
• 
Number of days from delivery 
• 
In case of miscarriage/ectopic - number of days from diagnosis 
 
Ultrasound data 
➢ Name of the ultrasound examiner 
➢ Ultrasound system used 
➢ Which modality used - transabdominal or transvaginal or transrectal 
➢ Mass detectable (yes/no; and if answer is ‘yes’) - pop-up: no ovary seen; ovary seen) 
➢ Ovarian or tubal or para-ovarian or uncertain? Left or right? 
 
Subjective assessment 
After ultrasonographic examination of the mass the investigator gives his/her subjective 
assessment of the mass: 
 
- 
A: Benign or Malignant (borderline or invasive) 
- 
B: Probability of malignancy (level of certainty / confidence with the diagnosis as being 
benign or malignant and managing it as that): 
1 = benign 
2 = probably benign 
3 = uncertain/not possible to classify 
4 = probably malignant (borderline / invasive) 
5 = malignant (borderline / invasive); 
- 
C: Self impression: presumed histological diagnosis (e.g. functional cyst; haemorrhagic 
corpus luteum cyst, pregnancy-associated cyst, theca-lutein cyst, teratoma, serous cystadenoma, 
mucinous cystadenoma, serous cystadenofibroma, mucinous cystadenofibroma, fibroma, 
endometrioma, decidualised endometrioma, abscess, hydrosalpinx, invasive - specify type, 
borderline - specify type; granulosa cell tumour, dysgerminoma, other); 
-  
D: Management: conservative management with ultrasound follow-up, surgery by 
general gynaecologist, surgery by oncological surgeon, other. 
- 
E: Any subjective ultrasound change to adnexal mass from previous scan (five options): 1) 
yes, change noted; 2) no change noted; 3) unsure (comment to explain why). 
- 
F: Colour score of ovarian mass: score 1, 2, 3, 4 

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- 
G: If papillations present: 1) number of papillations; 2) three orthogonal diameters (mm) 
of largest papillary projection i.e. height, base 1 and base 2; 3) smooth rounded papillations - 
yes / no; 4) colour in papillation - score 1, 2, 3, 4 (choose worst case scenario in case of multiple 
papillations). 
 
ADNEX Variables 
➢ Age 
➢ Oncology Centre (yes/no) 
➢ Maximum diameter of the lesion (mm) 
➢ Maximum diameter of largest solid component 
➢ Number of papillary projections (0, 1, 2, 3, > 3) 
➢ Presence of more than 10 cyst locules (yes/no) 
➢ Acoustic shadows (yes/no) 
➢ Presence of ascites (yes/no) 
➢ CA125 level (NOT TO BE MEASURED AT FOLLOW-UP SCANS) 
 
Modified Benign Simple Descriptors (tick images) 
1. Unilocular cyst with ground-glass echogenicity in premenopausal woman with largest 
diameter < 10 cm  
2. Unilocular cyst with mixed echogenicity and acoustic shadows in premenopausual woman 
with largest diameter < 10 cm  
3. Unilocular anechoic cyst with smooth internal cyst walls and largest diameter < 10 cm  
4. All other unilocular cysts with smooth internal cyst walls and largest diameter < 10 cm  
 
Ultrasound features suggestive of a complication of adnexal mass: no /yes 
- pop-up list (you can select more than one): 
o Suspected torsion 
o Infection/abscess 
o Haemorrhage 
o Rupture 
o Other, please specify:  …. 
 
Management data 
 
• 
Suggested management: “What type of management do you propose for this patient 
based on ultrasound subjective assessment?” 
o Conservative management with continued follow-up as per decision of clinician 
(data not to be used for this study); 
o Surgery by a gynaecologist or general surgeon; 
o Surgery by an oncological surgeon; 
o Mass is no longer present and only a normal ovary is seen - end of follow-up and 
completion of study; 
o Other (specify). 
 
 
 
 

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Appendix 5 – Outcomes (non-ultrasound) 
 
General 
 
➢ Patient decides to stop participating in the study (please specify why: …..) (no other pop-
up) 
➢ Patient withdraws her consent (data cannot be used for statistical analysis and no 
reason is asked) (no other pop-up) 
➢ Lost to follow-up 
 
Complications from the mass during pregnancy?  
 
Yes/No (pop up list) with number of episodes (one pop up per episode):  
▪ 
Acute pain 
▪ 
Chronic pain 
▪ 
Suspected torsion 
▪ 
Pelvic infection 
▪ 
Cyst rupture with haemorrhage (ultrasound diagnosis) 
▪ 
Cyst rupture without haemorrhage (ultrasound diagnosis) 
▪ 
Underwent surgery for a mass-related incident but mass not removed 
If Yes - type of surgery and findings: 
▪ 
Other, please specify:  …. 
 
Surgery (give option for more than one option) 
 
• 
Gestational age at surgery or number of days postpartum when surgery done 
 
• 
Type of operation: 
o Laparotomy with vertical incision  
o Laparotomy with horizontal incision 
o Operative laparoscopy  
o Diagnostic laparoscopy 
o Robotic surgery 
o Biopsy followed by neo-adjuvant chemotherapy (NACT) 
o Other (specify.............................)  
 
• 
Surgery performed: 
o Cyst drainage  
o Cystectomy/tumour resection 
o Oophorectomy 
o Salpingectomy 
o Salpingo-oophorectomy 
o Hysterectomy with cystectomy/tumour resection 
o Hysterectomy with salpingo-oophorectomy 
o Hysterectomy with oophorectomy 
o Hysterectomy with salpingectomy 
o Adhesiolysis 

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o Biopsy 
o Other: specify.........  
 
• 
Indication for operation (more than one possibility may be ticked): 
o Suspicion of malignancy based on ultrasound 
o Suspicion of malignancy based on other information; if so, which?  
o Acute / chronic pain 
o Suspected torsion 
o Suspected cyst rupture 
o Patient request  
o Increase in size of the tumour 
o Indicated 
by 
other 
imaging 
technique 
(suspicion 
of 
malignancy 
or 
torsion/haemorrhage/rupture) 
o Opportunistic removal of the mass when patient was operated for another 
indication  
o Opportunistic  removal of the mass during a C/Section  
o Other: Specify:  …. 
 
• 
Findings at operation (more than one option may be ticked): 
o No tumour found 
o No complications of the tumour 
o Torsion of mass 
o Rupture of mass 
o Inflammation/Infection 
o Adhesions 
o Bleeding from tumour 
o Disseminated carcinosis 
o Omental cake 
o Other complications of tumour: specify: …. 
o Other non-gynaecological pathology (e.g. appendicitis): specify:  …. 
 
• 
Complications (intra-operative, 0-30 days, >30 days post-operative; more than one 
option may be ticked) with specification on when complication occurred: 
o Conversion from laparoscopy to laparotomy 
o Bowel perforation 
o Bleeding requiring transfusion 
o Pulmonary embolism or deep venous thrombosis 
o Wound-related issues 
o Urine infection 
o Chest infection 
o Pre-term labour and delivery 
o Fetal complications (specify) 
o Other: Specify:  …. 
 
• 
Histological diagnosis (pop-up list as before) with open text area (“Details”):  
 
Benign tumour:  

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o Normal adnexa 
o Simple cyst 
o Functional cyst 
o Haemorrhagic corpus luteum cyst  
o Endometrioma  
o Teratoma (benign) 
o Fibroma 
o Thecoma 
o Serous cystadenoma 
o Mucinous cystadenoma 
o Serous cystadenofibroma 
o Mucinous cystadenofibroma 
o Paraovarian/parasalpingeal cyst 
o Hydrosalpinx 
o Other: .........  
Rare benign tumour: 
o Struma ovarii 
o Brenner tumour (benign)  
o Schwannoma 
o Other: ........  
Infectious (acute/chronic):  
                  o Abscess 
                  o Salpingitis  
o Other: .......... 
 
Uterine lesion:  
o Fibroid 
o Other: ...........  
 
Borderline tumours: 
o Serous borderline 
o Mucinous endocervical borderline 
o Mucinous gastrointestinal borderline 
o Other: ..........  
 
- FIGO stage: 
o I  
o II 
o III 
o IV 
o Not known 
o Not applicable 
  
 
 
 
 

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Primary invasive malignant tumour:  
 
Epithelial ovarian cancer  
o Serous HGSOC (high grade serous ovarian cancer) OR LGSOC (low grade serous 
ovarian cancer)  
o Mucinous 
o Endometrioid 
o Clear cell 
o Small cell carcinoma  
o Other: ..........  
FIGO stage: 
o I 
o II 
o III 
o IV 
o Not known 
o Not applicable  
 
Malignant germ cells tumour of the ovary  
o Immature teratoma 
o Dysgerminoma 
o Choriocarcinoma 
o Yolk sac/ Endodermial sinus tumour  
o malignant mixed germ cell tumor 
o embryonal carcinoma 
o Other: ........  
FIGO stage: 
o I 
o II 
o III 
o IV 
o Not known 
o Not applicable  
 
Stromal and sex-cord and steroid cell tumours of the ovary  
o Granulosa-adult 
o Granulosa-juvenile  
o Sertoli 
o Sertoli-Leydig 
o Sclerosing stromal cell tumour 
o steroid cell tumour NUD 
o Leydig  
FIGO stage: 
o I 
o II 
o III 
o IV 

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o Not known 
o Not applicable  
 
Other: 
o Fibrosarcoma 
o Carcinosarcoma 
o Other:.............  
FIGO stage: 
o I 
o II 
o III 
o IV 
o Not known 
o Not applicable  
 
Tubal cancer: 
o Serous  
o Mucinous 
o Endometrioid 
o Clear cell 
o Small cell carcinoma  
o Other: .........  
FIGO stage: 
o I 
o II 
o III 
o IV 
o Not known 
o Not applicable  
 
Metastatic malignant tumour: 
o Krukenberg  
o Metastasis from breast cancer 
o Metastasis from gastrointestinal tumour  
o Lymphoma 
o Other:..........  
 
Very rare malignant tumour: 
o 
Malignant struma ovarii 
o 
Or Specify...............  
 
FIGO stage: 
o I 
o II 
o III 
o IV 
• 
Not applicable 

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• 
Not known 

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Appendix  6 – Data Processing Agreement (DPA) 
 
This data processing agreement, including any annexes hereto, (together the "Data Processing 
Agreement") is an integrated part of this Protocol.  
All defined terms within the Agreement shall have the same meaning when used in this Data 
Processing Agreement, unless explicitly defined otherwise in this Data Processing Agreement. 
1. 
SCOPE OF THE DATA PROCESSING AGREEMENT 
1.1 
Each participating centre  acts as a data processor as defined under article 4, 8) of the 
Regulation (EU) 2016/679 (“Data Processor”) for the Sponsor who acts as data 
controller as defined under article 4, 7) of the Regulation (EU) 2016/679 (“Data 
Controller”), as each participating centre  processes Personal Data for the Sponsor as set 
out in Annex 1. 
1.2 
“Applicable Law”  means any applicable data protection or privacy laws, including  
(a) the Regulation (EU) 2016/679 also referred as the General Data Protection 
Regulation ("GDPR"),  
(b) other applicable laws that are similar or equivalent to or that are intended to or 
implement the laws that are identified in (a) of this definition,  
1.3 
"Personal Data" means any information relating to an identified or identifiable natural 
person (‘Data Subject’), including without limitation pseudonimized information, as 
defined in Applicable Law and described in Annex 1. 
2. 
PROCESSING OF PERSONAL DATA 
2.1 
Instructions: The Data Processor is instructed to process the Personal Data for the term of 
this Data Processing Agreement and only for the purposes of providing the data 
processing tasks set out in Annex 1. The Data Processor may not process or use Personal 
Data for any purpose other than a Data Subject’s medical records, or other than provided 
in the instructions, including with regard to transfers of personal data to a third country 
or an international organization, unless the Data Processor is required to do so according 
to Union or Member State law. In that case, the Data Processor shall inform the Data 
Controller in writing of that legal requirement before processing, unless that law prohibits 
such information on important grounds of public interest. 
2.2 
Data Processor shall at all times maintain a record of processing of Personal Data in 
accordance with Applicable Law and if the Data Processor considers an instruction from 
the Data Controller to be in violation of the Applicable Law, the Data Processor shall 
promptly inform the Data Controller in writing about this. 
3. 
THE DATA PROCESSOR'S OBLIGATIONS 
3.1 
The Data Processor must ensure that persons authorized to process the Personal Data 
have committed themselves to confidentiality or are under an appropriate statutory 
obligation of confidentiality. 
3.2 
The Data Processor shall implement appropriate technical and organizational measures to 
prevent that the Personal Data processed is: 

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i. 
accidentally or unlawfully destroyed, lost or altered, 
ii. 
disclosed or made available without authorization, or 
iii. 
otherwise processed in violation of Applicable Law.  
3.3 
The Data Processor must also comply with the special data security requirements of 
Annex 1. 
3.4 
The appropriate technical and organizational security measures must be determined with 
due regard for: 
i. 
the current state of the art, 
ii. 
the cost of their implementation, and 
iii. 
the nature, scope, context and purposes of processing as well as the risk of 
varying likelihood and severity for the rights and freedoms of natural persons. 
3.5 
The Data Processor shall upon request provide the Data Controller with sufficient 
information to enable the Data Controller to ensure that the Data Processor's obligations 
under this Data Processing Agreement are complied with, including ensuring that the 
appropriate technical and organizational security measures have been implemented. 
3.6 
Taking into account the nature of the processing, the Data Processor shall assist the Data 
Controller, by means of appropriate technical and organizational measures, insofar as this 
is possible, in fulfilling its obligation to respond to requests from Data Subjects pursuant 
to laws and regulations in the area of privacy and data protection (such as, the right of 
access, the right to rectification, the right to erasure, the right to restrict the processing, 
the right to data portability and the right to object). 
3.7 
The Data Controller is entitled to appoint at its own cost an independent expert, 
reasonably acceptable to Data Processor, who shall have access to the Data Processor's 
data processing facilities and receive the necessary information for the sole purpose of 
auditing whether the Data Processor has implemented and maintained said technical and 
organizational security measures. The expert shall upon the Data Processor's request sign 
a non-disclosure agreement provided by the Data Processor, and treat all information 
obtained or received from the Data Processor confidentially, and may only pass on, after 
conferral with Data Processor, the findings as described under article 3.9, (ii) below to the 
Data Controller. 
3.8 
The Data Processor must give authorities who by Union or Member State law have a right 
to enter the Data Controller's or the Data Controller's processors’ facilities, or 
representatives of the authorities, access to the Data Processor's physical facilities against 
proper proof of identity and mandate, during normal business hours and upon reasonable 
prior written notice. 
3.9 
The Data Processor must without undue delay in writing notify the Data Controller about: 
i. 
any request for disclosure of Personal Data processed under the Agreement by 
authorities, unless expressly prohibited under Union or Member State law, 
ii. 
any  finding of (a) breach of security that results in accidental or unlawful 
destruction, loss, alteration, unauthorized disclosure of, or access to, Personal 
Data transmitted, stored or otherwise processed by the Data Processor under the 
Agreement, or (b) other failure to comply with the Data Processor's obligations 
under Clause 3, or 

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iii. 
any request for access to the Personal Data (with the exception of medical 
records for which the Data Processor is considered data controller) received 
directly from the data subjects or from third parties. 
3.10 Such a notification from the Data Processor to the Data Controller with regard to a breach 
of security as meant in Clause 3.9 (ii)(a) will contain at least the following information: 
i. 
The nature of the Personal Data breach, stating the categories and (by 
approximation) the number of Data Subjects concerned, and stating the 
categories and (by approximation) the number of the personal data registers 
affected (datasets); 
ii. 
The likely consequences of the Personal Data breach; 
iii. 
A proposal for measures to be taken to address the Personal Data breach, 
including (where appropriate) measures to mitigate any possible adverse effects 
of such breach. 
The Data Processor shall document (and shall keep such documentation available for the 
Data Controller) any Personal Data breaches, including the facts related to the Personal 
Data breach, its effects and the corrective measures taken. After consulting with the Data 
Controller, the Data Processor shall take any measures needed to limit the (possible) 
adverse effects of Personal Data breaches (unless such consultation cannot be awaited 
due to the nature of the Personal Data breach). 
3.11 The Data Processor must promptly and reasonably assist the Data Controller (with the 
handling of (a) responses to any breach of security as described in 3.9 (ii) above and (b) 
any requests from Data Subjects under Chapter III of the GDPR, including requests for 
access, rectification, blocking or deletion. The Data Processor must also reasonably assist 
the Data Controller by implementing appropriate technical and organizational measures 
for the fulfilment of the Data Controller's obligation to respond to such requests. Any 
reasonable documented costs and expenses pre-approved in writing by the Data 
Controller related to the above will be reimbursed by the Data Controller to the extent 
such costs and expenses are not related to any requirements according to Applicable Law 
imposed on the Data Processor or due to any breach of this Appendix 6 or the Agreement 
by Data Processor.  
3.12 The Data Processor must reasonably assist the Data Controller with meeting the other 
obligations that may be incumbent on the Data Controller according to Union or Member 
State law where the assistance of the Data Processor is implied, and where the assistance 
of the Data Processor is necessary for the Data Controller to comply with its obligations. 
This includes, but is not limited to, at the request to provide the Data Controller with all 
necessary information about an incident under Clause 3.9 (ii), and all necessary 
information for an impact assessment in accordance with Article 35 and Article 36 of the 
GDPR. Any reasonable documented costs and expenses pre-approved in writing by the 
Data Controller related to the above will be reimbursed by the Data Controller to the 
extent such expenses are not related to any requirements according to Applicable Law 
imposed on the Data Processor or due to breach of this Appendix 6 or the Agreement by 
Data Processor. 
4. 
SUBPROCESSORS 
4.1 
The Data Processor may only engage a subprocessor, with prior specific or general 
written consent from the Data Controller. At the time of this Data Processing Agreement, 
the Data Processor uses the subprocessor listed in Annex 2. The Data Processor 

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undertakes to inform the Data Controller of any intended changes concerning the addition 
or replacement of a subprocessor by providing a reasonable prior written notice to the 
Data Controller. The Data Controller may reasonably and in a duly substantiated manner 
object to the use of a subprocessor. The Data Processor must inform the Data Controller in 
writing of the discontinued use of a subprocessor. 
4.2 
Prior to the engagement of a subprocessor, the Data Processor shall conclude a written 
agreement with the subprocessor, in which at least the same data protection obligations 
as set out in this Data Processing Agreement shall be imposed on the subprocessor, 
including obligations to implement appropriate technical and organizational measures 
and to ensure that the transfer of Personal Data is done in such a manner that the 
processing will meet the requirements of the Applicable Law. 
4.3 
The Data Controller has the right to receive a copy of the relevant provisions of Data 
Processor's agreement  with the subprocessor related to data protection obligations. The 
Data Processor shall remain fully liable to the Data Controller for the performance of the 
subprocessor obligations under this Data Processing Agreement. The fact that the Data 
Controller has given consent to the Data Processor's use of a subprocessor is without 
prejudice for the Data Processor's duty to comply with this Data Processing Agreement. 
5. 
CONFIDENTIALITY 
5.1 
The Data Processor shall keep Personal Data confidential. 
5.2 
The Data Processor shall not disclose the Personal Data to third parties or take copies of 
Personal Data unless strictly necessary for the performance of the Data Processor's 
obligations towards the Data Controller according to this Data Processing Agreement, and 
on condition that whoever Personal Data is disclosed to is under the responsibility of a 
professional subject to the obligation of professional secrecy under Union or Member 
State law or rules established by national competent bodies or by another person also 
subject to an obligation of secrecy under Union or Member State law or rules established 
by national competent bodies. 
5.3 
The Data Processor shall ensure that its employees comply with this Data Processing 
Agreement. 
5.4 
The Data Processor shall limit the access to Personal Data to employees for whom access 
to said data is necessary to fulfil the Data Processor's obligations towards the Data 
Controller. 
5.5 
The obligations of the Data Processor under Clause 5 shall continue until such time as 
provided by Applicable Law and regardless of whether the cooperation of the parties has 
been terminated. 
6. 
TERM AND TERMINATION OF THE DATA PROCESSING AGREEMENT 
6.1 
Regardless of the expiry or termination, for whatever reason, of the Agreement, this Data 
Processing Agreement remains in force and applicable as long as the Data Processor 
processes the Personal Data for the Data Controller under the Agreement. 
 

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6.2 
In case of termination of the Agreement, the Data Processor must provide the necessary 
transition services to the Data Controller. The Data Processor is obliged to reasonably 
assist Data Controller at Data Controller’s expense. 
Data Processor shall have appropriate procedures in place for the archiving of the 
Personal Data after the end of the Study in accordance with Applicable Law and at the end 
of the legally mandated archiving period ensure the destruction of the Personal Data and 
promptly inform Data Controller of this same.   
6.3 
If the Data Processor is required based on Union or Member State law to retain all or part 
of the Personal Data for a longer period than is possible based on the period mentioned in 
the Data Processing Agreement, the Data Processor shall immediately communicate this 
to the Data Controller, stating the basis, term and scope of such obligation. Once 
compliance with the obligation is no longer impeded by Union or Member State law, the 
Data Processor shall as yet erase the data in accordance with the provisions in the Data 
Processing Agreement. 
Annexes: 
Annex 1: 
Instructions 
Annex 2: 
Subprocessors 

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Annex 1 – Instructions 
This Annex 1 constitutes the Data Controller's instruction to the Data Processor in connection 
with the Data Processor's Personal Data processing for the Data Controller, and is an integrated 
part of the Data Processing Agreement. 
Contact details of the Data Controller (including its Data Protection Officer, if applicable): 
dpo@uzleuven.be 
Contact details of the Data Processor (including its Data Protection Officer, if applicable):  
[insert DPO per each participating centre] 
The processing of Personal Data 
a) 
Purpose and nature of the processing operations 
Performance of Clinical Study services under the Agreement and for the purpose of 
mandatory safety monitoring– as specifically described in the Protocol. 
i. 
Transfer of Personal Data to another country: Yes 
ii. 
If YES to I., transfer outside the EU AND EEA: No 
b) 
Categories of Data Subjects 
i. 
Former, current or future persons and/or patients who voluntarily enrolled in 
the Study, and/or their relatives, and/or 
ii. 
Data described in this Protocol 
c) 
Categories of Personal Data 
Re b) I: Date of birth and/or age, initials, personal identification number assigned to 
Data Subjects participating in the Study, description of characteristics of physical features 
of the body 
Re b) II:  Data described in this Protocol. 
d) 
Special categories of Personal Data 
Re b) I: Health information including past medical history and medical test information 
(such as blood samples results from scans and biopsies), data revealing racial or ethnic 
origin, genetic data and/or social security number 
e) 
Addresses of all locations of all participating centres where the processing will be 
performed are listed above in the first pages of the Protocol. 
f) 
Specific security requirements  
The following requirements reflect the minimum data processing requirements expected 
of the Data Processor. It is a condition that other agreed documents, legislation or 
industry standards laying down requirements of the processing of Personal Data in 
connection with Study/ /mandatory safety monitoring are complied with as well. 

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1. 
The Personal Data may only be used for the Study and/or mandatory safety 
monitoring.  
2. 
The collection, registration and other processing of Personal Data must be legally 
authorized under Applicable Law, or applicable policies issued of the supervisory 
authorities. 
3. 
Any person who takes part in the processing of Personal Data must be familiar with 
these requirements.  
4. 
Premises used for the storage and other processing of Personal Data must be 
arranged in such a way as to prevent unauthorized access.  
5. 
Appropriate security measures must be implemented to protect data against 
accidental or unlawful destruction, loss or impairment. Furthermore, it must be 
ensured that no incorrect or misleading Personal Data is processed. Incorrect or 
misleading data, or data processed in contravention of the above Applicable Law, 
policy of the supervisory authority or these requirements, shall be rectified or 
erased.  
6. 
Personal Data may not be stored in a way that makes it possible to identify the Data 
Subjects for longer than is necessary for the achievement of the Study and/or 
mandatory safety monitoring.  
7. 
The publication of results from clinical studies must take place in such a way that it 
is impossible to identify individual persons.  
8. 
It is a condition that other legislation laying down requirements of the processing of 
Personal Data in connection with Study and/or mandatory safety monitoring is 
complied with.  
Electronic data 
9. 
Identification data must be encrypted or replaced by a code number or similar. 
Alternatively, all data stored can be encrypted. Encryption keys, code keys, etc. must 
be stored securely and separately from the Personal Data. This also applies to 
Personal Data that is stored on portable devices such as laptop PCs, tablets, etc.  
10. 
Data may only be accessed by using a unique user name and a confidential 
password. The password must be renewed at least once a year and when otherwise 
necessary in order to ensure the secure processing of the data.  
11. 
On the transfer of Personal Data via the internet or other external networks, the 
necessary security measures must be taken to ensure that the Personal Data does 
not come to the knowledge of any unauthorized persons. This includes that 
encryption is required if sensitive Personal Data is transferred via the internet (or 
other open networks), and security of authenticity (identities of transmitter and 
recipient) and integrity (the authenticity of the transmitted Personal Data) must be 
appropriately ensured by the use of suitable security measures. On using internal 
networks, it must be ensured that no unauthorized persons can gain access to the 
data.  
12. 
Removable storage media, safety copies of Personal Data, etc. must be stored 
securely and under lock and key, so that unauthorized access is prevented.  

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Manual ("paper") data  
13. 
Manual material, including print-outs, error and control lists, etc. with Personal 
Data, must be stored securely under lock and key, and in such a way as to prevent 
unauthorized access.  
Biobank and biological material 
14. 
Samples with biological material and biological material in biobanks must be stored 
securely under lock and key so as to prevent unauthorized access, and in such a way 
as to ensure that the material is not lost, impaired, or accidentally or illegally 
destroyed.  
15. 
Biological material collected for the purpose of the Study and marked with a civil 
registration number or name must be stored subject to special safety requirements.  
16. 
Internal guidelines must be laid down within the Data Processor’s organization 
regarding the project for the storage of biological material.  
Information to be given to the clinical Studyparticipant/Data Subject 
17. 
Where the Personal Data is obtained from the clinical Study participant/Data 
Subject (via interviews, questionnaires, clinical or para-clinical examination, 
treatment, observation, etc.), more detailed information concerning the clinical 
Study/testing/safety monitoring shall be distributed/forwarded to the Data Subject 
in accordance with Article 13 of the GDPR. The clinical Study participant must, via 
the notification or informed consent form (as applicable) as approved by the 
relevant ethics committee and /or relevant authorities, be informed of the name of 
the Data Controller, the purpose of the trial/testing/safety monitoring, the fact that 
it is voluntary to participate in the trial/testing, the identity of any recipients of 
Personal Data, and the purpose of the disclosure of Personal Data, as well as any 
further information which is necessary for the clinical Study participant / Data 
Subject to be able to safeguard his/her interests. The Data Subject has been 
informed about the right of access to the Personal data that is processed concerning 
the person in question. 
Disclosure 
18. 
Disclosure/issue of Personal Data to other parties may take place to the extent that 
this is legally authorized under Applicable Law.  
On the conclusion of the project 
19. 
At the latest on the conclusion of the trial/testing/safety monitoring the Personal 
Data (including biological material) shall be erased, made anonymous, or destroyed, 
unless Union or Member State law requires continued storage of the Personal Data. 
In accordance with Belgian Law as defined in the Agreement the Data Processor 
shall be allowed to store the medical records for 30 years.  It must not subsequently 
be possible to identify individuals participating in the clinical Study/testing/safety 
monitoring. The deletion of Personal Data must be properly documented. 
20. 
Alternatively, the Personal Data may be transferred for further storage in archives 
according to the Data Controller’s instructions. Any costs related to such transfer 
and further storage of Personal Data shall be borne by the Data Controller. 

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21. 
Erasure of Personal Data from electronic media shall take place in such a manner 
that it is impossible to recover the Personal Data and such erasure must be properly 
documented. 
 
Annex 2 – Sub-processors 
The Data Controller agrees that the Data Processor – subject to compliance with Clause 4 of the 
Data Processing Agreement – engages the parties listed below as subprocessors. 
None