Van Wessel Steffi - Optimizing Hysteroscopic Treatment

OPTIMIZING
HYSTEROSCOPIC
TREATMENT
Steffi van Wessel

OPTIMIZING HYSTEROSCOPIC TREATMENT
Steffi van Wessel

Cover Design Bart Spiessens | Flanger Studios | www.flanger.org
Layout Bart Spiessens | Flanger Studios | www.flanger.org & Steffi van Wessel
Printing Ridderprint | www.ridderprint.nl
Financial support for the publication and defense was kindly provided by:
Nordic Pharma, Stöpler, Gedeon Richter, Ceres-pharma, Vésale Pharma
© Steffi van Wessel, 2023

All rights reserved. No part of this book may be produced in any form by any means, without
prior permission of the author.
OPTIMIZING HYSTEROSCOPIC TREATMENT
Steffi van Wessel

Student number: 00605643
Supervisors
Prof. Dr. Steven Weyers, Prof. Dr. Benedictus Schoot, Prof. Dr. Jan Bosteels
A dissertation submitted to Ghent University in partial fulfilment of the requirements for the degree of Doctor in Health
Sciences.
Academic year: 2022 - 2023

PROMOTORS
Prof. Dr. Steven Weyers
Department of Obstetrics and Gynecology, Ghent University Hospital (Belgium)
Prof. Dr. Benedictus Schoot

Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven (The Netherlands)
Prof. Dr. Jan Bosteels

Department of Obstetrics and Gynecology, Imelda Ziekenhuis, Bonheiden (Belgium)
GUIDANCE COMMITTEE
Prof. Dr. Tjalina Hamerlynck
EXAMINATION COMMITTEE
Prof. Dr. Marc Coppens
Department of Anesthesiology, Ghent University Hospital (Belgium)
Prof. Dr. Wouter Froyman

Department of Obstetrics and Gynecology, University Hospital Leuven (Belgium)
Dr. An-Sofie Goessaert

Department of Urology, Ghent University Hospital (Belgium)
Prof. Dr. Mark Hans Emanuel

Women’s Care, Bergman Clinics, Hilversum and Department of Reproductive Medicine and
Gynecology, University Medical Center, Utrecht (The Netherlands)
Prof. Dr. Björn Heindryckx

Department of Reproductive Medicine, Ghent University Hospital (Belgium)
Dr. Frauke Vanden Meerschaut

Department of Reproductive Medicine, Ghent University Hospital (Belgium)
Dr. Noortje van Oostrum

It always seems impossible untill it’s done.
(Nelson Mandela)
TABLE OF CONTENTS
Abbreviations..........................................................................9
Chapter 1............................................................................... 11
General introduction
Chapter 2............................................................................... 27
Objectives and outline of the thesis
Part I Pain relief in office diagnostic hysteroscopy
Chapter 3............................................................................... 35
Efficacy of oral nifedipine, naproxen, or placebo for pain relief during diagnostic
hysteroscopy in an office setting: a randomized pilot study
J Minim Invasive Gynecol. 2023 Feb 16:S1553-4650(23)00058-4
Part II Instrumentation for operative hysteroscopy
Chapter 4............................................................................... 51
Hysteroscopic morcellation versus bipolar resection for removal of type 0 and 1
submucous myomas: A randomized trial
Eur J Obstet Gynecol Reprod Biol. 2021;259:32-7
Chapter 5............................................................................... 65
Manual morcellation (Resectr™ 9fr) versus electromechanical morcellation (Truclear™) for
hysteroscopic polypectomy: a randomized controlled non-inferiority trial
Acta Obstet Gynecol Scand. 2023;102:209-217
Chapter 6............................................................................... 81
Clinical evaluation of a new hand driven hysteroscopic tissue removal device, Resectr™ 5fr,
for the resection of endometrial polyps in an office setting
Arch Gynecol Obstet. 2023 Mar 15.
Part III Reproductive outcome after operative hysteroscopy
Chapter 7............................................................................... 99
Reproductive and Obstetric Outcomes After Hysteroscopic Removal of Retained Products of
Conception
J Minim Invasive Gynecol. 2020;27(4):840-6
Chapter 8............................................................................. 113

Anti-adhesion Gel versus No gel following Operative Hysteroscopy prior to Subsequent fer-
tility Treatment or timed InterCourse (AGNOHSTIC), a randomised controlled trial: protocol
Hum Reprod Open. 2021;2021(1):hoab001
Chapter 9............................................................................. 131

General discussion
Summary.............................................................................. 145
Samenvatting......................................................................... 149
References............................................................................ 153
About the author..................................................................... 163
Publications........................................................................... 165
Addenda............................................................................... 167
Dankwoord............................................................................ 171
7
ABBREVIATIONS
AUB Abnormal Uterine Bleeding
CI Confidence Interval
D&C Dilation and Curettage
ESGE European Society for Gynaecological Endoscopy
ESHRE European Society of Human Reproduction and Embryology
Fr French (= diameter in millimeters x 3)
FIGO International Federation of Gynecology and Obstetrics
IDEAL Idea, Development, Exploration, Assessment, Long-term study
ISGE International Society for Gynecologic Endoscopy
IUA IntraUterine Adhesions
IUD Intrauterine Device
MAUDE Manufacturer and User Facility Device Experience
MD Mean Difference
NaCl Sodium Chloride
NSAIDs Non-Steroid Anti-Inflammatory Drugs
OR Odds Ratio
PBAC Pictorial Blood Assessment Chart
RCT Randomized Controlled Trial
RPOC Retained Products Of Conception
SIS Saline Infusion Sonography
STEPW Size, Topography, Extension, Penetration, lateral Wall position
TENS Transcutaneous Electrical Nerve Stimulation
VAS Visual Analogue Scale
9
CHAPTER 1
General introduction
12 | CHAPTER 1
1
DEFINITIONS
Hysteroscopy is a minimally invasive method in which a hysteroscope is used

to visualize the vagina, cervix and uterine cavity. Nowadays, hysteroscopy is
the gold standard for diagnosis and treatment of intrauterine pathology, and
both can be performed simultaneously (‘see and treat’ approach) (1,2).
During a diagnostic hysteroscopy, evaluation takes place of the

aforementioned anatomical regions, with or without targeted biopsy (3). It
is performed to investigate the origin of abnormal uterine bleeding (AUB),
to elucidate abnormal findings seen on other imaging exams or in the
fertility work-up (4).
An operative hysteroscopy allows to treat intrauterine pathology (Figure 1),

under direct hysteroscopic visualization using hysteroscopic instruments (3).
For example, intrauterine device (IUD) removal or replacement, intrauterine
pathology removal, or endometrial resection in case of AUB
(i.e. endometrial ablation) (1).
In an ambulatory model of care the patient is admitted to a facility and
discharged on the same calendar day (3). Whereas in an office or
outpatient model of care, the patient arrives and leaves a medical
practitioner’s premises or a facility, respectively, on the same calendar day.
The last two terms are often used interchangeably. The setting in which
these procedures are performed, and the anesthesia used varies.
Figure 1 Intrauterine pathology
A B C
D E F
A. Endometrial polyp B. Fibroid C. Uterine septum D. Retained products of conception
E. Intrauterine adhesions F. IUD dislocation (personal collection)
CHAPTER 1 | 13
MILESTONES
The historical milestones in the development of hysteroscopy are shown in

addendum 1. Hysteroscopy is in its origin closely related to cystoscopy, but
the latter had a faster development since it is easier to distend the bladder
with a high liquid capacity. The development of hysteroscopy was slowed
by inadequate light transmission, narrowness of the uterine cavity with the
inability to distend it properly, fragility of the endometrium causing
mucosal bleeding, and the necessity to rinse the uterine cavity with a
distension medium to allow clear visualization.
Innovations in hysteroscopic procedures only started in the mid 90’s, with

the introduction of alternative energy sources (bipolar electrosurgery and
mechanical energy), small diameter hysteroscopes and instruments, and
procedures being performed in the office setting.
Modern hysteroscopy anno 2023 consists of a video camera and monitor, a

cold light source, a light cable, saline for uterine distension administered
using gravity (90-100 cm above the perineal plane), a pressure bag (80-120
mmHg) or an automated fluid management system, and a rigid hysteroscope
with continuous flow (1). Rigid compared to flexible hysteroscopes cause
more discomfort, but provide superior optical quality and are less expensive
(5).
HYSTEROSCOPIC INSTRUMENTS
Mechanical 5 french (Fr) instruments (Figure 2) have long been the only
option for operative hysteroscopy. These instruments are introduced into
the uterine cavity through a 5 Fr working channel of an operative
hysteroscope with a total outer diameter ranging from 4.0 to 5.0 mm.
The main limitation of this type of instrument is the ratio between the size
of the resected pathology and the diameter of the internal cervical ostium
which may impede tissue removal (6,7). A larger pathology size is
associated with more additional maneuvers for tissue extraction, longer
operating times, and higher pain scores when performed in an office setting.
Moreover, 5 Fr mechanical instruments have a limited degree of movement,
are fragile, lack electrosurgery which hampers hemostasis, and swirling
tissue chips may compromise visualization.
In 1989 the resectoscope became available. This device consists of a

working element, an inner and an outer sheath, and an electrode suitable
for electrosurgery (Figure 3). The loop electrode is most used, but several
other electrodes, both disposable and reusable, are available.
Initially, monopolar electrosurgery was used to treat intrauterine pathology.
It requires grounding of the patient, so that current can flow through the
body, and a non-electrolytic solution for uterine distension (8,9).
14 | CHAPTER 1
1
Figure 2 5 Fr mechanical instruments
© KARL STORZ SE & Co. KG, Germany (used with permission)
The latter is associated with a risk of serious complications such as fluid

overload with electrolyte disorders (hyponatremia), pulmonary edema,
congestive cardiac failure, cerebral edema and even death (9,10).
Therefore, fluid deficit should be limited to 1000 ml.
Later on, bipolar electrosurgery was developed, in which the current is
returned by a neutral electrode in proximity of the conducting electrode
(8). Therefore, an isotonic solution, sodium chloride (NaCl), can be used
which limits the risk of fluid overload with electrolyte disorders and allows
for a larger deficit up to 2500 ml, with more time to resect intrauterine
pathology (10,11). Hysteroscopic bipolar resectoscopes are available in
varying diameters (ranging from 14.9 Fr to 26 Fr).
Nevertheless, the resectoscope continued to be associated with some
drawbacks: there was a rather long learning curve, a suboptimal view
because of the formation of gas bubbles and swirling tissue chips, and the
necessity of reinsertions of the hysteroscope or additional instruments to
remove tissue which increases the risk of uterine perforation and air
embolism.
Figure 3 Resectoscope
© KARL STORZ SE & Co. KG, Germany (used with permission)
CHAPTER 1 | 15
In 1995, Ivan Mazzon described an alternative use of the hysteroscopic
resectoscope in which electric current was omitted (cold loop) (12). Specific
electrodes have been developed for this purpose, but the existing electro-
surgical electrodes can simply be used non-activated.
In 1997, 5 Fr bipolar instruments were developed, featuring two disposable

electrodes: the Twizzle Tip electrode (precise and controlled vaporization,
needle-like cutting) and Spring Tip electrode (wider vaporization and
desiccation) (Figure 4). They are compatible with the same hysteroscopes
used for 5 Fr mechanical instruments. The advantages are the small
instrument size, the use of bipolar energy, and the possibility to overcome
swirling tissue chips through vaporization (though leaving no tissue available
for pathology analysis). Nevertheless, the disadvantages of 5 Fr mechanical
instruments and the bipolar resectoscope are still applicable (6,13).
Figure 4 5 Fr bipolar instruments
A B
A. Twizzle Tip electrode B. Spring Tip electrode

Versapoint™ II (Olympus) (used with permission)
In 2005, the mechanical hysteroscopic tissue removal system became

available, with the aim of resolving some of the disadvantages related to
the existing instruments (Figure 5) (14). The device consists of an outer
hollow and an inner rotating sheath with corresponding windows at the end
for simultaneous tissue cutting and aspiration. A foot pedal activates the
motor that drives the blade inside the hysteroscope and a vacuum source is
used for tissue aspiration. The proposed advantages are a clear view, less
complications (uterine perforation, gas embolism and thermal damage) and
immediate removal of intrauterine tissue (14,15). Moreover, there seems to
be a short learning curve (15,16). On the contrary, there might be impaired
hemostasis related to mechanical energy, there is the cost of disposable
instruments and the limited durability of reusable instruments.
The terminology of this device has a history on itself. Initially, it was called
‘the intrauterine morcellator’, but in 2014 there was a shift towards
‘mechanical hysteroscopic tissue removal system’ to avoid misunderstanding
with laparoscopic power morcellation (14,17). The latter was issued a black
box warning because of the risk of dissemination of malignancy in case of
hidden uterine sarcomas. Although, it was concluded that there is no risk
with the use of hysteroscopic morcellators, the term ‘intrauterine
16 | CHAPTER 1
1
morcellation’ has been abandoned. ‘Hysteroscopic shaver’ is a frequently
used synonym.
Figure 5 Mechanical hysteroscopic tissue removal system
TruClear™ Elite Hysteroscopic tissue removal system (Medtronic) (used with permission)
The latest innovation in the field of hysteroscopic tissue removal systems is

a manually driven device for polypectomy. The electrically powered
control unit is replaced by a hand piece in order to simplify the procedure.
In 2016, the Resectr™ (MinervaSurgical, USA; previously Boston Scientific,
USA) became available in 2 sizes (5 Fr and 9 Fr) (Figure 6). Each squeeze in
the hand piece initiates six turning movements of the inner blade
(3 rotations clockwise, followed by 3 rotations counterclockwise).
During each turn, the inner blade can cut tissue. An aspiration pump,
activated with a foot pedal, is used for controlled suction of the resected
tissue. The Resectr™ is compatible with the 5 Fr and 9 Fr working channels
of the existing mechanical hysteroscopic tissue removal systems.
In 2018, Hologic (USA) developed the MyoSure MANUAL, but there is no data
available on its clinical use until date.
Meanwhile, several manufacturers have developed mechanical hysteroscopic
tissue removal systems, with specific devices adapted to the different tissue
characteristics (addendum 2).
Figure 6 Manual hysteroscopic tissue removal device
Resectr™ (MinervaSurgical) (used with permission)
CHAPTER 1 | 17
Moreover, two hybrid devices, combining bipolar electrosurgery with active
tissue aspiration have been developed: the Resection Master (2005, Richard
Wolf, Germany) and the Symphion™ Tissue Removal System (2014,
MinervaSurgical, USA). Apart from two abstracts, no studies are available on
these hybrid devices (18,19). The working mechanism, though, seems
somewhat contradictory: while with the hysteroscopic resectoscope one
tries to obtain large tissue chips to speed up the procedure, with these
instruments the chips need to be small enough to be suitable for aspiration
through the device.
HYSTEROSCOPIC TREATMENT OF INTRAUTERINE PATHOLOGY
The choice of the instrument depends on several factors: type, location and
size of the intrauterine pathology, the available instrumentation and
operator’s experience.
Endometrial polyps are focal endometrial outgrowths containing glands,

stroma and blood vessels (20). Fibroids derive from myometrial cells and
they are classified according to their anatomical location (International
Federation of Gynecology and Obstetrics (FIGO) Leiomyoma Subclassification
System) (21). Fibroids suitable for hysteroscopic resection are submucous
fibroids type 0, 1 and 2 (entirely within the uterine cavity, <50% and ≥50%
myometrial extension, respectively), and intramural fibroids sufficiently
large to distort the uterine cavity (hybrid fibroids type 2–5). The extent of
cavity protrusion is clinically relevant for predicting the successful outcome
of hysteroscopic fibroid removal (22).
Instruments that have been used for polyp and fibroid removal are the 5 Fr
mechanical and bipolar instruments, and the resectoscope using both
electrosurgery and cold loop (12,23).
Mechanical hysteroscopic tissue removal systems have been examined
mainly for polyp and fibroid removal. At the start of our research, three
meta-analyzes had been performed comparing the mechanical hysteroscopic
tissue removal system with electrosurgical resection (both 5 Fr bipolar
electrodes and resectoscope included) for the removal of polyps and type 0
and 1 fibroids (24–26). Subgroup analysis of data derived from
randomized controlled trials (RCTs) revealed a significantly shorter operating
time for the mechanical hysteroscopic tissue removal system (mean
difference (MD) 4.5 minutes). Subgroup analysis per pathology however
showed only a benefit for the removal of polyps. Overall, the complete
removal rate was in favor of the mechanical hysteroscopic tissue removal
system, the complication rate was not significantly different, whereas the
fluid deficit was inconclusive. Nevertheless, these meta-analyzes have some
shortcomings: limited number of studies, polyps and fibroids have different
tissue characteristics relating differently to the uterine cavity, different
brands and diameters of devices were included with possibly different
resection rates, 5 Fr bipolar electrodes and the resectoscope involve a
18 | CHAPTER 1
1
different technique, and lastly the primary outcome, operation time, had
different definitions.
Retained products of conception (RPOC) consist of intrauterine tissue that

develops after conception and persists after pregnancy (including
miscarriage, termination of pregnancy, vaginal delivery, or cesarean section)
(27). In 1997, Goldenberg et al published the first report on the use of
hysteroscopy to remove RPOC using a cold loop (28). In 2013, Hamerlynck et
al described the use of the mechanical hysteroscopic tissue removal system
as an alternative approach for the removal of RPOC (29). In 2016, a RCT was
performed comparing mechanical hysteroscopic tissue removal with loop
resection (30). Resection rates were in favor of the mechanical
hysteroscopic tissue removal system. Both techniques were safe with high
rates of complete removal and low de novo intrauterine adhesion rates.
In addition, 5 Fr mechanical instruments can also be used for smaller RPOC
(1). However, anno 2023, there is no consensus regarding the standard
approach of RPOC, and dilation and curettage (D&C) is still widely used (31).
Meta-analysis of cohort studies shows that compared with D&C, cold loop
resection is associated with a lower incidence of intrauterine adhesions
(30% versus 13%, respectively) and more complete evacuation (71% versus
99%, respectively) (32). However, RCTs should still confirm this (NTR4923,
NCT04705324).
A uterine septum is a congenital uterine malformation. According to the

European Society of Human Reproduction and Embryology (ESHRE)/
European Society for Gynaecological Endoscopy (ESGE) classification system
for female genital tract congenital anomalies, it is defined as a uterus with
a normal outline and an internal indentation at the fundal midline
exceeding 50% of the uterine wall thickness (Class U2) (33).
Different instruments (5 Fr mechanical and bipolar instruments, the
resectocope and mechanical hysteroscopic tissue removal system) have been
used to perform hysteroscopic septum resection and there is insufficient
evidence for the superiority of one instrument (34,35).
Intrauterine adhesions (IUAs) are fibrous strings at opposing walls of the

uterus, developing after injury to the basal layer of the endometrium
(36,37). IUAs are an indication for, but may also be a consequence of
hysteroscopic treatment. The main risk factor for IUA development is the
gravid uterus (miscarriage with or without curettage, postpartum
curettage, post abortion or postpartum endometritis, ischemic phenomena
after postpartum hemorrhage and uterine artery embolization) (38).
Different instruments (5 Fr mechanical and bipolar instruments and the
resectoscope) have been used to perform hysteroscopic adhesiolysis (39).
None of these instruments have been compared with each other,
consequently, there is no evidence to recommend a specific instrument.
However, mechanical instruments should be preferred owing to the
potential risk for further endometrial damage.
CHAPTER 1 | 19
FROM OPERATING ROOM TO OFFICE (OR OUTPATIENT)
HYSTEROSCOPY
In the 90’s interest arose in performing hysteroscopy in an office setting.

The first RCT comparing office diagnostic hysteroscopy with that performed
in the operating room showed that, along with a similar rate of patient
satisfaction, women subjected to office hysteroscopy, had a significantly
shortened duration of recovery (40). Later, the feasibility of office
hysteroscopy was proven in large cohort studies (7,41–47).
Research addressing blind and hysteroscopic polypectomy determined the
non-inferiority of the outpatient setting compared to procedures performed
in the operating room for symptom improvement (48). A significant
difference in mean resection time, complete removal rate, and adverse
event rate could not be observed between polyp and fibroid removal
performed in the operating room and in the outpatient setting using a
mechanical hysteroscopic tissue removal system (49). Moreover, women with
AUB and polyps had a preference to be treated in the outpatient setting
(50).
An economic evaluation has been performed for hysteroscopic polypectomy

(51,52). The outpatient setting was more cost-effective than
procedures performed in the operating room owing to reduced staff, no
need for hospital stays and operating room facilities, and a faster return
to normal activities. The use of non-disposable instruments, in particular
cutting loop electrodes, is the most cost-effective approach in both settings,
but it requires skilled
surgeons. The shorter surgical time and the shorter learning curve related to
the use of mechanical hysteroscopic tissue removal systems should be taken
into consideration when performing hysteroscopic polypectomy.
Nevertheless, the outpatient setting is still not widely used because of fear
of pain and complications, the belief that special expertise is required,
and in many countries the lack of a financial incentive. The latter has been
shown in a questionnaire among Flemish and Dutch gynecologists in 2016
(53).
OPTIMIZING PATIENT COMFORT DURING OFFICE HYSTEROSCOPY
The uterus is innervated by two main pathways (54). The sympathetic

nerves derive from T10 to L2 and enter the fundus via the superior
hypogastric plexus, the hypogastric nerve, the inferior hypogastric plexus
and the uterovaginal plexus. The parasympathetic nerves derive from S2 to
S4 and enter the upper vagina, the cervix and the lower uterine segment via
the sacral plexus, and the lower vagina and vulva via the pudendal nerve.
The sensitive innervation in the uterus mainly relates to the myometrium,
originating from the plexus at the myometrial-endometrial interface. This is
20 | CHAPTER 1
1
the rationale ensuring that the hysteroscopic procedure can be performed
without any analgesia or anesthesia, provided that some basic rules to avoid
patient discomfort are respected.
Pain during hysteroscopy arises from vaginal speculum insertion,
tenaculum placement, cervical dilation, the passage of the hysteroscope
through the cervical canal, especially at the level of the internal cervical
orifice, myometrial contractility induced by uterine cavity distension or
direct stimulation when the uterine wall is touched by the hysteroscope or
the instrument, and disruption of the endometrium because of removal of
intrauterine pathology (54–56).
A consensus on optimal method of pain relief in the office setting is

lacking and various methods have been described (oral analgesics (non-
steroid anti-inflammatory drugs (NSAIDs), opioids) and local anesthetics
(intracervical injection, paracervical injection, intrauterine instillation,
ectocervical application)) (56,57). For diagnostic hysteroscopy there is no
consistent, good-quality evidence of a clinically meaningful difference in
safety or effectiveness of pain relief methods (57). However, local
anesthetics may be considered when performing a diagnostic or an operative
hysteroscopy in postmenopausal women to reduce the failure rate related to
pain (58).
Different strategies have emerged to maximize patient comfort during out-

patient hysteroscopy.
Miniaturization of hysteroscopes is associated with lower pain scores.
Meta-analyzes, comparing mini-hysteroscopes (≤ 3.5 mm) with 5 mm
hysteroscopes, showed lower pain scores when using mini-hysteroscopes
(59). However, subgroup analysis comparing mini-hysteroscopes with
different diameters (3 mm, 3.3 mm and 3.5 mm) did not affect pain scores.
There might be a cut off around 3.5 mm below which reduction of scope size
might not further reduce pain.
Vaginoscopy includes a direct introduction of the hysteroscope through
visualization of the vagina and cervix, and hydrodistension of the cervix
(60,61). The hysteroscope is guided into the fornix posterior, then it is
pulled backed and introduced into the external cervical orifice.
The cervical anatomy should be followed by gentle movements of the
hysteroscope maintaining the vision of the cervical canal at 6 o’clock in the
case of a 30° optic.
Saline is the preferable method for uterine distension (62). There is no
significant difference in pain when using CO2 as distension medium.
However, meta-analysis revealed that vasovagal episodes, shoulder tip pain
and procedural time were significantly reduced when using saline. Moreover,
image quality is better as it causes a lavage and thus prevents blood and
bubbles from obscuring the view. Lastly, it is suitable for operative
hysteroscopic procedures using bipolar electrosurgery. Warming saline
(37.5°C) did not significantly reduce pain.
The intrauterine pressure needed for uterine distension should be as low as
possible to allow clear visualization and kept below the mean arterial
CHAPTER 1 | 21
pressure (ranging 70 – 110 mmHg) in order to minimize fluid deficit and
reduce pain (10,62). In clinical practice, intrauterine pressures are rarely
measured for practical reasons and adjustments are usually made on the
external pressure applied on the distension medium through pressure bags
or automated pumps (63).
Cervical preparation using prostaglandins is associated with reduced pain,
easier entry, and reduced procedural time (64). However, this should be
weighed against the increased side effects (bleeding, abdominal cramping,
gastro-intestinal disturbances).
OPERATIVE HYSTEROSCOPY FOR AUB
There is a lack of high-quality studies evaluating the clinical outcomes of

hysteroscopic polypectomy in women with AUB (65,66). Data derived from
observational studies suggest symptom improvement in 75-100% of the
women within a follow-up period of 2 to 52 months. A RCT in pre-
menopausal women with polyps, comparing hysteroscopic resection with
expectant management, could not observe a significant difference in
Pictorial Blood Assessment Chart (PBAC) at 6 months follow-up (67).
However, not all the included women suffered from AUB, and
intermenstrual bleeding decreased significantly after hysteroscopic
polypectomy. A RCT comparing hysteroscopic polypectomy with expectant
management in women with postmenopausal bleeding, a thickened
endometrium (> 4.0 mm) and benign endometrial sampling, could not
demonstrate a significant difference in bleeding recurrence after 1 year
(68). However, (pre)malignancy was detected in 6% of the hysteroscopy
group. Outpatient polypectomy versus polypectomy performed in the
operating room (including blind and hysteroscopic procedures) did not differ
significantly in alleviating AUB at 6 months follow-up (overall 77%) (48). The
treatment effect was maintained at 12 and 24 months. The retrospective
comparison of 5 Fr mechanical and bipolar electrodes and the resectoscope
on the one hand, and mechanical hysteroscopic tissue removal systems on
the other hand could not identify a significant difference in AUB recurrence
during 4 years of follow-up (overall 23%) (69). Premenopausal status, history
of hormone replacement therapy, multiparity, and polycystic ovarian
syndrome were independently associated with AUB recurrence.
In summary, the management of polyps remains unclear. Most women appear
to have symptom alleviation after polypectomy, but it is uncertain whether
the removal of the lesion is associated with this desirable outcome.
The success rate of hysteroscopic fibroid removal to alleviate AUB ranges

from 70 to 99% with a follow-up period up to 8 years (12). The longer the
follow-up period, the lower the success rate, which could be attributed to
incomplete fibroid removal or the occurrence of other factors causing AUB.
The reported 3-year cumulative fibroid recurrence rate was 34% and the
3-year cumulative AUB recurrence rate was 30% (70). The risk for additional
surgery was 21% after 4 years follow-up, and 0% thereafter (71).
22 | CHAPTER 1
1
Furthermore, with a mean follow-up of 2.6 years, the overall symptom
improvement was 91% and the overall patient’s satisfaction was 86%.
Moreover, it has been shown that incomplete fibroid removal does not
always necessitate subsequent surgery (72,73).
OPERATIVE HYSTEROSCOPY IN WOMEN WISHING TO CONCEIVE
Several intrauterine pathologies, including endometrial polyps, fibroids with

uterine cavity deformation, uterine septa, RPOC and IUAs have been linked
with female fertility problems (74–77). The evidence in favor of operative
hysteroscopy for improving reproductive success is sparse and of moderate
to low quality (76,78,79). Nevertheless, hysteroscopy is very often
performed, especially in women attending fertility clinics because among
the medical community the presence of intrauterine pathology distorting
the uterine cavity is widely believed to impair reproductive outcome.
A major long-term complication of operative hysteroscopy is the formation

of IUAs (30,38,80). The reported incidence of postsurgical IUAs at second-
look hysteroscopy is 3.6% after polypectomy, 6.7% after resection of uterine
septa, 31% after removal of a solitary fibroid, 45% after resection of multiple
fibroids and 3% after removal of RPOC.
Hysteroscopic adhesiolysis aims to restore the uterine anatomy.
Unfortunately, IUA reformation may occur in around 28.7% of patients (38).
Reviews of large observational studies have demonstrated an association
between IUAs and poor reproductive outcome, namely a prevalence of
infertility as high as 43.0% and recurrent pregnancy loss in 22.0% (36,80,81).
Moreover, there is an increased risk of obstetric complications even after
successful hysteroscopic adhesiolysis, for example abnormal placentation,
preterm delivery, uterine rupture and peripartum hysterectomy (82).
RPOC are a special entity because the gravid uterus is more sensitive to
develop IUAs (38). The reported prevalence of IUAs after D&C to treat
miscarriage is 19% (83). Moreover, women with more than one miscarriage
were found to have significantly more IUAs than women with only one
miscarriage. While the available evidence originates from small cohort
studies with a poor-average methodological quality, similar reproductive
outcomes were reported in a meta-analysis comparing D&C with loop
resection using hysteroscopy (32). Nevertheless, there is insufficient
evidence on how different treatment options for RPOC affect future
reproductive outcomes (79).
The only RCT comparing a mechanical hysteroscopic tissue removal system
with loop resection showed low de novo intrauterine adhesion rates (3%) in
both groups (30). The reproductive and obstetric outcome after RPOC
removal by mechanical hysteroscopic tissue removal systems has not yet
been reported.
CHAPTER 1 | 23
Women of reproductive age wishing to conceive may benefit from IUA
prevention following operative hysteroscopy. Different methods to prevent
IUAs after operative hysteroscopy have been assessed: mechanical barriers
(IUD, intrauterine balloon, and anti-adhesion gel) and agents stimulating
endometrial regeneration (hormonal treatment and human amniotic
membrane grafting). A Cochrane meta-analysis of five RCTs has
demonstrated that the use of an anti-adhesion gel may decrease the
occurrence of IUAs at second-look hysteroscopy compared to no treatment
or placebo (odds ratio (OR) 0.37, 95% confidence interval (CI) [0.21–0.64];
P<0.01) (84). The overall quality of the body of evidence retrieved was low
and data on live birth rates were lacking.
Other anti-adhesion strategies have been suggested, but need further
investigation (85). Namely, the adherence to an appropriate hysteroscopic
technique in which the use of electrosurgery is reduced, damage to the
healthy endometrium and myometrium surrounding the lesion is avoided and
forced cervical manipulation is avoided. Furthermore, an early post-
operative second-look hysteroscopy (1-2 weeks after surgery).
24 | CHAPTER 1
1
CHAPTER 1 | 25
CHAPTER 2
Objectives and outline of the thesis
28 | CHAPTER 2
OBJECTIVES
Hysteroscopy is an important method for diagnosing and treatment of AUB

and in the fertility work-up. It was our goal to explore innovations that
1
could improve hysteroscopic practice: 2
- How can we improve pain relief during office diagnostic hysteroscopy?
- Is it feasible to use mechanical hysteroscopic tissue removal systems in

the removal of fibroids?
- Are manually driven hysteroscopic tissue removal devices a good

alternative for polypectomy?
- What is the reproductive and obstetric outcome after hysteroscopic RPOC

removal comparing mechanical hysteroscopic tissue removal with loop
resection?
- Is the use of an anti-adhesion gel after operative hysteroscopy effective in

improving reproductive outcomes?
OUTLINE
In chapter 3, a pilot RCT is performed to compare nifedipine with NSAIDs or

placebo for pain relief during diagnostic hysteroscopy in an office setting.
Calcium channel blockers relax vascular smooth muscle cells by preventing
calcium from entering the cells (86). The dihydropyridines (nifedipine) cause
vasodilation and are used in cardiovascular treatment.
The pharmacologic characteristics imply it may also have a relaxing effect
on the uterine smooth muscle cells, and therefore may decrease the
myometrial contraction-related pain (87,88). It is used off-label for the
treatment of preterm labor (89,90). Nifedipine as pain relief during
hysteroscopy has not yet been studied, and has several advantages: oral
administration, few contra-indications, and a low cost.
In chapter 4, a RCT comparing the mechanical hysteroscopic tissue

removal system (Truclear™ ultra plus) with the hysteroscopic resectoscope
using bipolar electrosurgery (26 Fr.) to resect submucous type 0 and 1
fibroids is discussed.
Chapter 5 gives the results of a randomized controlled non-inferiority trial
CHAPTER 2 | 29
comparing the manual (Resectr™ 9 Fr.) with the electromechanical
hysteroscopic tissue removal device (Truclear™ incisor mini) for the
resection of polyps.
In chapter 6, the results of a prospective cohort study are discussed, using

the small variant of the manual hysteroscopic tissue removal device
(Resectr™ 5 Fr.) for the resection of polyps in an office setting without
anesthesia.
In chapter 7, the results of a follow-up study are shown, evaluating the

reproductive and obstetric outcome in women treated for RPOC by
hysteroscopy, comparing the mechanical hysteroscopic tissue removal
system (Truclear™ incisor plus) with loop resection (26 Fr.).
In chapter 8, the protocol of the ongoing AGNOHSTIC trial (Anti-adhesion

Gel versus No gel following Operative Hysteroscopy prior to Subsequent
fertility Treatment or timed InterCourse, a RCT) is presented. Intrauterine
adhesions following operative hysteroscopy impair reproductive success in
women of reproductive age. Anti-adhesion barrier gels may decrease the
occurrence of intrauterine adhesions, but the evidence on their
effectiveness to improve reproductive outcomes is sparse and of low quality.
30 | CHAPTER 2
1
2
CHAPTER 2 | 31
PART I
PAIN RELIEF IN OFFICE DIAGNOSTIC HYSTROSCOPY
CHAPTER 3
Efficacy of oral nifedipine, naproxen,
or placebo for pain relief during diagnostic
hysteroscopy in an office setting:
a randomized pilot study
Steffi van Wessel

Julie Rombaut
Astrid Vanhulle
Mark Hans Emanuel
Tjalina Hamerlynck
Steven Weyers
J Minim Invasive Gynecol. 2023 Feb 16:S1553-4650(23)00058-4

ABSTRACT
Study Objective To compare nifedipine, naproxen, or placebo for pain relief

during diagnostic hysteroscopy.
Design Double-blind randomized controlled pilot study.
Setting University hospital.
Patients Women scheduled for office diagnostic hysteroscopy (n=60).
Interventions Women received nifedipine (2 tablets of 10 mg), naproxen (2

tablets of 250 mg) or placebo (2 tablets of 500 mg lactose) 30 – 60 minutes
prior to hysteroscopy.
Measurements and Main Results Sixty patients were enrolled in the study
(21 in the nifedipine group, 19 in the naproxen group, and 20 in the placebo
group) The median pain scores during hysteroscope insertion, measured on
a Visual Analogue Scale (VAS), were 1 (interquartile range (IQR) 0-0), 2 (0-4)
and 1 (0-1) in the nifedipine, naproxen and placebo group, respectively
(P .14). The median VAS scores during hysteroscopy were 5 (IQR 2-7), 5 (4-8)
and 5 (3-7) in the nifedipine, naproxen and placebo group, respectively
(P .73). The median VAS scores immediately after hysteroscopy were 2
(IQR 0-4), 3 (0-6) and 3 (1-5) in the nifedipine, naproxen and placebo group,
respectively (P ,40). The median VAS scores 30 minutes after hysteroscopy
were 1 (IQR 0-2), 1 (0-1) and 1 (0-2) in the nifedipine, naproxen and placebo
group, respectively (P .63). Hysteroscope insertion failed in 1 case
(naproxen group) because of cervical stenosis (P .32). Flushes, fatigue and
vertigo, thirty minutes after the procedure, were significantly more
prevalent in the nifedipine group compared to the naproxen (P <.001, P .03,
P .03, respectively) and the placebo group (P <.001, P .01, P .01,
respectively). Palpitations occurred only in the nifedipine group (P <.001).
The day after the procedure, headache was most prevalent in the nifedipine
group compared to the naproxen group (P .001) and the placebo group
(P .001).
Conclusion In our pilot study, pain relief and success rates for office
diagnostic hysteroscopy were not significantly different between nifedipine,
naproxen and placebo. Nifedipine was associated with more, albeit
tolerable, side-effects.
36 | CHAPTER 3
INTRODUCTION
Hysteroscopy is the gold standard for diagnosis and treatment of

intrauterine pathology. Miniaturization and enhancements of hysteroscopes
and hysteroscopic instruments have enabled procedures to be safely and
effectively performed in office (1–3). Moreover, compared to the ambulatory
setting, office hysteroscopic procedures are equally acceptable to patients
and recovery is quicker (4).
Strategies to maximize patient comfort include: the use of saline, the

vaginoscopic approach, and cervical ripening with misoprostol in selected
3
patients (5–9).
A consensus on optimal method of pain relief for office hysteroscopy

however is lacking and various methods have been described: oral analgesics
(non-steroid anti-inflammatory drugs (NSAIDs), opioids), and local
anesthetics (intracervical, paracervical, intrauterine instillation,
ectocervical application). For diagnostic hysteroscopy there is no
consistent, good-quality evidence of a clinically meaningful difference in
safety or effectiveness of pain relief methods (10). However, local
anesthetics may be considered when performing a diagnostic or an operative
hysteroscopy in postmenopausal women to reduce the failure rate related to
pain (11).
Calcium channel blockers relax vascular smooth muscle cells by

preventing calcium from entering the cells (12). The dihydropyridines
(nifedipine) cause vasodilation and are used in cardiovascular treatment.
The pharmacologic characteristics imply it may also have a relaxing effect
on the uterine smooth muscle cells, and therefore may decrease the
myometrial contraction-related pain (13,14). It is used off-label for the
treatment of preterm labor (15,16). Nifedipine as pain relief during
hysteroscopy has not yet been studied, and has several advantages: oral
administration, few contra-indications, and low cost.
The aim of this pilot randomized controlled trial (RCT) is to compare

nifedipine with NSAIDs or placebo for pain relief during office diagnostic
hysteroscopy.
MATERIAL AND METHODS
This double-blinded pilot RCT was performed at the Ghent University

Hospital (Belgium) from May 2019 to June 2022. The study was approved
by the Ethical Committee and registered at the Dutch Clinical Trial Registry
(NTR NL 7750), amendments to speed up inclusions made during the trial
can be found at EudraCT (https://www.clinicaltrialsregister.eu/ctr-search/
trial/2018-001020-19/BE) (preprocedural blood pressure ≥ 100 mmHg
CHAPTER 3 | 37
systolic instead of 120mmHg and BMI < 35 kg/m² instead of 30 kg/m²). All
women gave written informed consent.
Women aged 18 – 50 years, scheduled for diagnostic hysteroscopy in an

office setting, with a BMI < 35 kg/m² and preprocedural blood pressure ≥
100 mmHg systolic and ≥ 60 mmHg diastolic were eligible for inclusion.
Exclusion criteria were menopause, cardiovascular diseases, hypotension
(systolic pressure <100 and/or diastolic pressure <60 mmHg), use of cardio-
vascular medication, pregnancy, breast feeding, liver diseases, daily use of
pain medication, gastric ulcers related to NSAIDs, use of CYP3A4-inhibitors,
rifampicin or magnesium sulfate.
The intervention is nifedipine (2 tablets of 10mg), a dihydropyridine, which

inhibits calcium influx and relaxes smooth muscle cells. It is short-acting
(Tmax (time to maximum serum concentration) 0.5-2 hours, T½ (time to
halve the serum concentration) 2-4 hours), it works in 20 minutes and it is
metabolized by CYP3A4. Common side-effects (< 10%) are malaise,
(peripheral) edema, vasodilation, obstipation, and headache.
The control is naproxen (2 tablets of 250mg) or placebo (2 tablets of 500mg

lactose). Naproxen, a propionic acid derivative, inhibits the prostaglandin
synthesis and is an analgesic, antipyretic and anti-inflammatory drug.
It is long-working (Tmax 2-4 hours, T½ 10-17 hours) and it works in 1 hour.
Common side-effects (1-10%) are reflux, nausea, stomachache, abdominal
pain, obstipation, headache, fatigue, dizziness, tinnitus, allergic skin
reaction, ecchymosis, decreased thrombocyte aggregation, prolonged
bleeding, peripheral edema, and dyspnea.
Patients were randomly assigned with a 1:1:1 allocation ratio, to

nifedipine (group A), naproxen (group B) or placebo (group C).
Randomization was done by a computer-generated random allocation
sequence (random.org). The treatment allocation was concealed by
sequentially, numbered, opaque, sealed envelopes kept by an
independent person. Both the patient, the gynecologist and the nurse
assisting the procedure were blinded for the treatment allocation. Within a
timeframe of 30 – 60 minutes before the diagnostic hysteroscopy, the blood
pressure was measured. Immediately thereafter, the randomization was
done by the study nurse and the patient received the treatment allocation
blindfolded.
The diagnostic hysteroscopy was performed by staff-members with similar

experience. The 4.3mm Bettocchi® hysteroscope (Karl Storz, Tuttlingen,
Germany) was used. Saline was used as distension medium and delivered by
a pressure bag. A vaginoscopic approach was used without cervical ripening.
After the procedure, the women were observed for 30 minutes to monitor
the blood pressure and possible side-effects. A telephone visit was scheduled
the following day to monitor side-effects.
38 | CHAPTER 3
The primary outcome was maximum pain intensity measured on a Visual
Analogue Scale (VAS) during hysteroscope insertion (from the vaginoscopy to
the insertion of the hysteroscope into the cervix just beyond the external
ostium), during the procedure (from beyond the external ostium until the
moment just before the hysteroscope was removed from the uterine cavity),
at the end of the procedure (just after complete removal of the
hysteroscope from the uterus), and 30 minutes after hysteroscopy.
The secondary outcomes were success rate, duration of the hysteroscopy,

hysteroscopy related complication rate, medication related side-effects 30
minutes and the day after the hysteroscopy, additional pain relief taken 3
until the day after the procedure, patient’s willingness to take the same
medication again (registered the day after the procedure).
Since this was a pilot study, without existing literature on which to base
accurate power calculations, no power calculation was performed.
The sample size for this pilot study was therefore determined at 60 women.
This study was performed to provide guidance for a future RCT.
Data were collected and managed using Research Electronic Data Capture
(REDCap) tools hosted at Ghent University Hospital (17,18). REDCap is a
secure, web-based software platform designed to support data capture for
research studies, providing an intuitive interface for validated data capture,
audit trails for tracking data manipulation and export procedures,
automated export procedures for seamless data downloads to common
statistical packages, and procedures for data integration and inter-
operability with external sources. Data were analyzed using the statistical
program SPSS (version 28, IBM Corp., Armonk, NY). Continuous variables
were summarized with descriptive statistics mean and standard deviation
for data normally distributed and median and interquartile range (IQR)
otherwise. Categorical data were presented as frequency and percentage.
Continuous data were analyzed using the One-way ANOVA test if the data
were normally distributed or using the Kruskal Wallis test otherwise.
Categorical data were analyzed using the Chi-square test or Fisher’s exact
test when numbers were small. The residuals from the linear regression
model of the primary outcome (VAS score) were not normally distributed,
therefore a Kruskal Wallis test was performed. Level of significance was set
at P < .05.
A per protocol analysis was performed to assess the robustness of our

findings, excluding any women that received their medication outside the
defined time frame. A safety analysis was also performed.
RESULTS
Sixty women were enrolled in the study (Figure 1). Patient characteristics
CHAPTER 3 | 39
are shown in Table 1. Women with complaints (fatigue, abdominal cramps,
headache, and procedure related stress) at the moment of the
administration of the allocated treatment were not significantly different
between the 3 groups (P .35).
Figure 1 Consort flowchart
Table 1 Patient characteristics
40 | CHAPTER 3
Data regarding the diagnostic hysteroscopy is shown in Table 2.
The introduction failed in 1 case of the naproxen group because of cervical
stenosis. The VAS scores at the start (P .14), during (P .73), at the end
(P .40) and 30 minutes after the diagnostic hysteroscopy (P .63) were not
significantly different between nifedipine, naproxen and placebo.
The proportion of women with a VAS score higher than 4 (57%, 61% and 60%)
was also not significantly different between the 3 groups (P 1.0). Overall,
the reported VAS scores were the highest during the diagnostic hysteroscopy.
The VAS scores at the other time points were low. In 6 cases additional
procedures (endometrial biopsy (pipelle) (n=4), placement of an
intrauterine device (IUD) (n=1), a vaginal examination (n=1)) were 3
performed subsequent to the diagnostic hysteroscopy. The median time
between administration of the allocated treatment and the hysteroscopy
was 77 minutes, 69 minutes, and 70 minutes in the nifedipine, naproxen and
placebo group, respectively. The diagnostic hysteroscopy was performed
outside the defined timeframe in 3, 6 and 4 women of the nifedipine (range
64 – 77 minutes), naproxen (range 64 – 79 minutes, with one procedure
being performed after 25 minutes) and placebo group, respectively, because
of practical matters (P .42).
Table 2 Diagnostic hysteroscopy
CHAPTER 3 | 41
The postprocedural data is shown in Table 3. The median systolic blood
pressure 30 minutes after the diagnostic hysteroscopy was 115 mmHg (IQR
109-123), 122 mmHg (113-132) and 119 (113-124) in the nifedipine,
naproxen and placebo group, respectively (P.19). The median diastolic blood
pressure 30 minutes after the diagnostic hysteroscopy was 71 mmHg (IQR 65-
77), 77 mmHg (69-81) and 76 mmHg (71-84), respectively (P .04). Subgroup
analysis showed a significant difference between nifedipine and placebo (P
.02). Flushes, fatigue and vertigo, thirty minutes after the procedure, were
significantly more prevalent in the nifedipine group compared to the
naproxen (P <.001, P .03, P .03, respectively) and the placebo group (P
<.001, P .01, P .01, respectively). Palpitations occurred only in the
nifedipine group (P <.001). The day after the procedure, headache was most
prevalent in the nifedipine group compared to the naproxen group (P .001)
and the placebo group (P .001).
Eleven women in the nifedipine group required additional medication for
pain in the postprocedure period (paracetamol, ibuprofen, excedrine or
diclofenac) compared to two women in the naproxen group (paracetamol or
ibuprofen (P .004) and five women in the placebo group (paracetamol)
(P .03).
The per protocol analysis led to similar conclusions.
Table 3 Postprocedural data
42 | CHAPTER 3
DISCUSSION
In our sample we could not observe a statistically nor clinically significant

difference between the randomization groups with respect to the mean
ranking on the VAS scale and the probability of a VAS score higher than 4.
Furthermore, the success ratio was high in all groups and not significantly
different. However, the use of nifedipine was associated with significantly
more side-effects and need for additional pain relief after the hysteroscopy.
Nevertheless, the side effects would not refrain more patients from taking
nifedipine again compared to naproxen or placebo.
3
To our knowledge, this is the first report on the use of nifedipine as
analgesic method for office hysteroscopy. Calcium channel blockers prevent
the passage of calcium into the muscle cells and prevent them from
contracting. Therefore, it has analgesic potential.
We report on a well-designed RCT, blinding the outcome assessor and the
participant and using an active reference treatment as well as a placebo.
An objective parameter, VAS score, was used to measure women’s pain
experience. Moreover, the VAS score was recorded on different time points,
up to 30 minutes after the hysteroscopic procedure. Furthermore, a safety
analysis was performed, taking medication related side-effects until the day
after the procedure into account.
We do acknowledge that our study has some limitations. An important

shortcoming is the small sample size and the lack of a sample size
calculation. Since nifedipine was never used before for the indication of
pain relief for hysteroscopy, our intention was to conduct a pilot study to
determine whether a larger multicenter RCT is worth the effort. The lack of
a statistically significant difference could be due to a lack of power.
However, the estimated differences for the probability of a VAS score higher
than 4 (57% in the nifedipine group, 61% in the naproxen group and 60% in
the placebo group) also do not seem to be clinically relevant. Another
shortcoming is the fact that in 6 cases additional procedures were
performed subsequent to the diagnostic hysteroscopy. This could have
influenced the VAS scores 30 minutes after the procedure.
However, these VAS scores were low and not significantly different.
The diagnostic hysteroscopy was performed outside the defined timeframe
in some cases, which is associated with day-to-day practice. Therefore, we
could have underestimated the analgesic potential of nifedipine and
naproxen. Still, pain relief was not different in the per-protocol analysis.
Uterine retroversion was significantly more prevalent in the placebo group
compared to the naproxen group (P .02). The retroverted position is a
known risk factor for pain during outpatient hysteroscopy (19). However, the
VAS scores were not significantly different. Some VAS scores at 30 minutes
were missing because they forgot to ask the patient. Lastly, the cervix itself
is formed mainly by connective tissue (20). Therefore, cervical pain (from
distension and manipulation) might be unresponsive to nifedipine.
CHAPTER 3 | 43
The literature regarding pain relief in office diagnostic and operative
hysteroscopy has expanded since the start of our study. The evidence for
conscious sedation, local anesthesia and analgesia, compared to no
treatment, placebo, the same, another or a different dose/scheme
analgesic or anesthetic, has been examined by De Silva and colleagues
(21–23). Conscious sedation and local anesthesia via any route of the genital
tract are not recommended routinely. Regarding analgesia, NSAIDs reduce
pain during and after the hysteroscopic procedures without an increase in
side-effects. The authors conclude that women without contraindications
should be advised to take oral NSAIDs before the hysteroscopic procedure,
although the optimal route, dose and timing of administration has yet to be
determined. Transcutaneous Electrical Nerve Stimulation (TENS), is
suggested as a suitable alternative for analgesia in case of contraindications
for NSAIDs. The technique of TENS is based on the stimulation of specific
dermatomes, which establishes a blockade at the dorsal horn, preventing
pain from being transmitted to the upper nervous system. The two studies
included in the meta-analysis of Da Silva and colleagues are heterogenous in
terms of TENS application (device, electrode placement and settings) (23–
25). Therefore, we could not report on TENS as a standardized technique.
Moreover, it entails logistical challenges (necessity of a specific device and
application before the procedure) when performed for office hysteroscopy.
A major limitation of the meta-analysis on analgesia of De Silva et al is the
methodologic and clinical heterogeneity of the studies included (23).
Hence, we believe more good quality data are needed before one can
recommend NSAIDs routinely.
Recently, a Cochrane review has been published on the use of Nifedipine for
pain relief in primary dysmenorrhea, which is the only gynecologic
indication so far (26). No new studies have been published since the start of
our trial. Compared to placebo, nifedipine was effective for pain relief (odd
ratio (OR) 9.04 95% confidence interval (CI) (2.61 – 31.31)),but the evidence
was of low-quality and based on only 2 studies. The adverse event rate did
not significantly differ from placebo (OR 0.94 95%CI (0.07 – 4.20) and the
most prevalent symptoms were headache and facial flushes.
The side-effects of nifedipine were expected, but the prevalence is higher

than those reported in literature. An observational study of 40 women using
nifedipine for severe, primary dysmenorrhea reported headache (38%),
palpitations (13%), vertigo (8%), nausea (5%) and diarrhea (3%) (13). Another
observational study of 10 women using nifedipine for severe, primary
dysmenorrhea reported an increased heart rate (100%), a decrease in
diastolic pressure and transient flushing (14). Unfortunately, the reason for
additional pain relief was not registered.
In our opinion future well-designed studies should focus more in detail on

the efficacy of different types of NSAIDs for pain relief during diagnostic
and operative hysteroscopy in an office setting. If the evidence for pain
relief increases, the optimal route, dose and timing of NSAIDs should be
determined. Subsequently, a well-designed large scale non-inferiority study
44 | CHAPTER 3
should be performed to study alternative analgesia, such as
nifedipine, which could offer an alternative to patients who cannot take
NSAIDs. Meanwhile, office diagnostic hysteroscopy without analgesia, taking
other pain-reducing strategies into account is acceptable for most women.
CONCLUSION
In our pilot study, pain relief and success rates for office diagnostic
hysteroscopy were not significantly different between nifedipine, naproxen
and placebo. Nifedipine was associated with more, albeit tolerable, side-
3
effects.
CHAPTER 3 | 45
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CHAPTER 3 | 47
PART II
INSTRUMENTATION FOR OPERATIVE HYSTEROSCOPY
CHAPTER 4
Hysteroscopic morcellation versus bipolar
resection for removal of type 0 and 1
submucous Myomas: a randomized trial
Steffi van Wessel

Hubertus van Vliet
Benedictus Schoot
Steven Weyers
Tjalina Hamerlynck
Eur J Obstet Gynecol Reprod Biol. 2021;259:32-7

ABSTRACT
Objectives To compare hysteroscopic morcellation with bipolar resection for

the removal of submucous type 0 and 1 myomas, in terms of procedure time
(primary outcome), adverse events, tissue availability,short term
effectiveness and postoperative adhesion formation (secondary outcomes).
Study design The study was performed from May 2011 to May 2018 in the
Catharina hospital (Eindhoven, the Netherlands) and the Ghent University
hospital (Ghent, Belgium). Women with type 0 and 1 submucous myomas up
to 3 cm were randomized to hysteroscopic morcellation with the TruClear™
8.0 Tissue Removal System or to bipolar resection with a rigid 8.5-mm
resectoscope. Skewed time variables were log-transformed and analyzed
with the Student t-test. Multiple linear regression analysis was performed to
assess the effect of myoma diameter on operating time.
Results Forty-five and 38 women were included in the hysteroscopic

morcellation and resection group, respectively. The median operating time
was significantly shorter for hysteroscopic morcellation compared with
resection (9.2 min [interquartile range 5.6–14.4] versus 13.4 min [inter-
quartile range 8.6–17.5], P = .04). In the morcellation group, operating
time, corrected for the myoma diameter, was reduced by 26 % (95 % CI
5–43%; P = .02). The median setup time was significantly longer in the
morcellation group (5.2 min [interquartile range 4.2–6.9] versus 3.8 min
[interquartile range 3.3–5.3], P = .006). The median total procedure time
was not significantly different between the two techniques (14.4 min
[interquartile range 11.4–19.2] versus 17.3 [interquartile range 12.7–23.8],
P = .18). Two procedures of the morcellation group were converted to
bipolar resection because of the myoma hardness. Complete resection was
found in 89 % of the morcellation group and 95 % of the resection group.
Adverse events occurred in 3 patients of the morcellation group, namely a
fluid deficit > 2500 mL with the need of potassium suppletion, an asystolic
vasovagal response after conversion to resection and postoperative fever
requiring antibiotics. Tissue was available for pathology analysis in all cases.
Routine second-look hysteroscopy performed in one center showed no intra-
uterine adhesions.
Conclusion Overall, there is no difference in total procedure time between

hysteroscopic morcellation using the TruClear™ system compared to bipolar
resection for the removal of smaller type 0 and 1 submucous myomas.
Although hysteroscopic morcellation is faster, its setup time is longer.
Calcified myomas can be challenging and fluid deficit remains a limiting
factor.
52 | CHAPTER 4
INTRODUCTION
Since the introduction of hysteroscopic surgery, submucous myomas were

preferably removed by the technique of hysteroscopic resection using
electrosurgery. Although monopolar current may be more effective in cutting
tissue, bipolar resection allows to use saline as irrigation fluid. The latter
limits the risk of electrolyte disorders and allows for a larger fluid deficit (up
to 2500 mL) and therefore more time to resect intrauterine pathology (1).
Nevertheless; hysteroscopic resection has some disadvantages, for example
a rather long learning curve, a suboptimal view because of the formation of
gas bubbles and swirling tissue chips, and the need to remove these chips by
reinsertions of the hysteroscope or additional instruments which increases
the risk of uterine perforation.
In 2005, hysteroscopic morcellation became available with the aim to

resolve some of these disadvantages (2,3). The device removes myomas 4
in a mechanical way by combining aspiration and cutting. In theory, this
technique would ensure a clear view and reduce the risk of complications
(uterine perforation, gas embolism and thermal damage). Because no chips
need to be removed and due to the improved visualization, hysteroscopic
morcellation might be a faster technique to remove intrauterine pathology
compared to hysteroscopic resection. To our knowledge, no studies have
been published which compare this technique with hysteroscopic resection
for removal of myomas.
The aim of this randomized controlled trial (RCT) was to compare the
hysteroscopic tissue removal system with traditional bipolar resection for
removal of submucous type 0 and 1 myomas in terms of procedure time,
as well as adverse events, tissue availability, short term effectiveness and
postoperative adhesion formation.
MATERIALS AND METHODS
This open label RCT was conducted at the Catharina Hospital (Eindhoven,
the Netherlands) and at the Ghent University Hospital (Ghent, Belgium),
from May 2011 to May 2018. Approval was obtained from both ethical
committees. The study was registered at Clinicaltrials.gov as part of a series
of studies comparing hysteroscopic morcellation and resection for the
removal of intrauterine pathologies (polyps, placental remnants and
myomas) (NCT01537822) (4,5). Written informed consent was required
before randomization.
Women were eligible when they had at least one submucous type 0 myoma
(entirely within the uterine cavity) or type 1 myoma (< 50 % myometrial
extension), measuring up to 3 cm and were scheduled for removal by
hysteroscopy. The diagnosis was made by ultrasound, saline infusion
CHAPTER 4 | 53
sonography (SIS) and/or diagnostic hysteroscopy. Exclusion criteria were
myomas with a larger diameter (> 3 cm), submucous type 2 myomas
(50 % myometrial extension), suspicion of malignancy, untreated cervical
stenosis, or the presence of a contraindication for operative hysteroscopy.
We assumed that hysteroscopic morcellation was not the ideal technique to
treat type 2 myomas because of their intramural extension (3). Moreover,
type 2 myomas and myomas larger than 3 cm often require several
procedures for complete removal (6).
Women were randomly assigned in a 1:1 ratio to hysteroscopic morcellation

or resection. A computer-generated random allocation sequence
(random.org) was used for randomization. Sequentially numbered, opaque,
sealed envelopes concealed the treatment allocation sequence, and were
kept by an independent person. After opening of the envelope, both the
researcher and the participant were informed on the allocated arm. The
Consolidated Standards of Reporting Trials 2010 statement for reporting of
RCTs was followed, and a flowchart is provided (Figure 1).
Figure 1 CONSORT flowchart
Allocation
Follow-up
Analysis
54 | CHAPTER 4
Hysteroscopic myomectomy was performed by staff-members with a similar
level of experience or skilled residents under direct supervision. Procedures
were performed in day surgery under spinal or general anesthesia or
conscious sedation. No cervical ripening agents were administered pre-
operatively. Antibiotic prophylaxis was administered according to local
practices.
Hysteroscopic myoma resection was performed with a rigid 8.5 mm bipolar

resectoscope (Karl Storz GmbH, Tuttlingen, Germany), equipped with a 12
or 30optic. Resection was carried out according to the slicing technique (3).
Hysteroscopic morcellation was performed with the TruClear™ 8.0 system
(previously: Smith & Nephew, Andover, MA, USA; currently: Medtronic,
Minneapolis, MN, USA), equipped with a 0optic and 9-mm sheath, using the
4.0 reciprocating blade. The technique of morcellation has been previously
described (5). With both techniques, the hysteroscope was introduced in
the uterine cavity after dilation of the uterine cervix with Hegar dilators up 4
to 9- or 10-mm. Normal saline was used for distention and irrigation of the
uterine cavity. Fluid balance was closely monitored using the Hysteroscopic
Fluid Management System (previously: Smith & Nephew, Andover, MA, USA;
currently: Medtronic, Minneapolis, MN, USA) with a maximum pressure
setting of 120 mmHg and a maximum flow setting of 700 mL/min for
hysteroscopic morcellation or the Hysteropump (Richard Wolf GmbH,
Knittlinen, Germany) with a maximum pressure setting of 150 mmHg and a
maximum flow setting of 450 mL/min for resection.
The primary outcome was time, namely setup time, operating time and
total procedure time. Setup time was defined as the time to set up the
hysteroscopic instrumentation ready for use. Time registration starts after
disinfection and drape placement, includes cervical dilation and ends when
the hysteroscopic device was ready to be inserted. Setup time was counted
separately because of the difference in setup between hysteroscopic
morcellation and resection (amount of tubings, blade alignment). Operating
time starts at introduction of the hysteroscope in the cervix until the time
at which the procedure was completed and the hysteroscope was removed
definitely. The sum of the setup and operating time resulted in the total
procedure time.
Secondary outcomes were fluid deficit, number of insertions of the

hysteroscope, conversion rates, completeness of resection, tissue
availability for pathology analysis, peri- and postoperative adverse events
(including perforation, fluid overload (deficit of > 2500 mL distention
medium with clinical consequences), electrolyte disturbances, bleeding,
burns, gas embolism, and infection). Also, data on short term effectiveness
(persistent symptoms or intrauterine pathology at 6 weeks follow-up visit),
and postoperative adhesions seen during routine second-look office
hysteroscopy (performed routinely only at the Ghent University hospital)
were documented. Intrauterine adhesions were classified as mild, moderate,
or severe according to the classification of Valle and Sciarra (7).
CHAPTER 4 | 55
The sample size was calculated according to the randomized controlled pilot
study of van Dongen et al. (8). The expected effect size was 0.7 based on a
6.4-minute difference in operating time between hysteroscopic morcellation
and resection to remove polyps and myomas. The calculated sample size to
find this difference by 2-sided independent Student t testing, with a
significance level of 0.05 and a power of 0.80 was 34 women in each group.
The statistical program SPSS version 26 (IBM SPSS Statistics 26.0, IBM Corp.,
Armonk, NY, USA) was used for data collection and analysis.
For normally distributed continuous variables, means, standard deviations,
and 95 % confidence intervals (CIs) were calculated and the mean
differences were analyzed using the Student t-test. For non-normally
continuous variables median, interquartile range (IQR) were reported, and
analysis was performed using the Mann-Whitney U test Categoric data are
presented as frequency and percentage and analyzed using the Fisher Exact
test. Skewed time variables were log-transformed and analyzed with the
Student t-test in order to compare geometric means. Multiple linear
regression analysis was performed to assess the effect of myoma diameter
on operating time because the myoma diameter is known to influence the
operating time. A p value of < .05 was considered to be statistically
significant. Both an intention-to-treat and per-protocol analysis were carried
out for the primary outcome.
RESULTS
Eighty-three women were randomized (Figure 1). Fifty-four women (65 %)

and 29 women (35 %) were treated in Catharina Hospital (Eindhoven, The
Netherlands) and the Ghent University Hospital (Ghent, Belgium),
respectively.
The baseline patient characteristics are shown in Table 1 and the pre-
operative symptoms, imaging and intraoperative myoma characteristics in
Table 2. No significant differences were found between the hysteroscopic
morcellation and resection groups.
Surgery data are presented in Table 3. The operating time was significantly
shorter in the morcellation group (P = .04), but the setup time was
significantly longer (P = .006). The total procedure time was not
significantly different between hysteroscopic morcellation and resection
(P = .18). Multivariate analysis taking the mean diameter of the largest
myoma into account showed that an increased diameter was associated with
longer operating times (P < .001). Correction for the diameter of the myoma
did not modify the significant difference in operating time between the 2
groups (P = .02). Operating time was still reduced by 26 % (95 % CI 5–43%) in
the morcellation group. Per-protocol analysis was performed in 68
women (Fig. 1) and the results were in line with those of the
56 | CHAPTER 4
intention-to-treat analysis.
In the morcellation group there were 2 conversions (4%) to resection

because of the hardness of the myoma. Complete removal of myomas was
achieved in 78 cases (94 %). Incomplete removal of myomas was found in 4
of 45 cases (9%) of the hysteroscopic morcellation group (conversion to
bipolar resection because of the hardness of the myoma: n = 2, fluid deficit
> 2500 mL combined with a type 2 myoma: n = 1 and suboptimal
visualization: n = 1) and in 1 of 38 cases (3%) of the resection group
(suboptimal visualization combined with a type 2 myoma: n = 1).
Tissue was available for pathology analysis in all cases. In the morcellation
group there were 3 (7%) adverse events. One patient had a fluid deficit >
2500 mL with the need of potassium replacement, the resection was
incomplete. She had no complaints and was discharged the same day.
An asystolic vasovagal response after conversion to resection occurred in
one woman after 800 mL intravasation. She was resuscitated and the 4
procedure could be continued. Nevertheless, there was an incomplete
resection because of the hardness of the myoma. The patient was admitted
to the medium care for observation and was discharged after 2 days. One
patient had postoperative fever requiring antibiotics. In the resection group
there were no adverse events. At follow-up visit, 12 of 43 women (28 %)
in the hysteroscopic morcellation group and 10 of 37 women (27 %) in the
resection group still suffered from abnormal uterine bleeding. Two out of 4
women with incomplete myoma removal in the hysteroscopic morcellation
group suffered from abnormal uterine bleeding postoperatively, the other
cases did not. Only one case of the incomplete resections in the
morcellation group needed additional treatment (laparoscopic
hysterectomy). Second-look hysteroscopy was performed in 14 out of 16
women in the morcellation group and in all women of the resection group at
the Ghent University hospital. No intrauterine adhesions were seen.
Table 1 Baseline patient characteristics
CHAPTER 4 | 57
Table 2 Preoperative symptoms, imaging and intraoperative myoma characteristics
Table 3 Surgery data
58 | CHAPTER 4
DISCUSSION
Our data showed that hysteroscopic morcellation using the TruClear™ system
is faster than bipolar resection for the removal of smaller type 0 and 1
myomas. Although the operating time of both techniques was relatively
short and with a longer setup time in the morcellation group, the overall
procedure time was the same for both techniques.
The shorter operating times related to hysteroscopic morcellation can be

explained by the simultaneous cutting and aspiration effect of the
hysteroscopic tissue removal system. Only a single insertion of the device is
needed to remove the intrauterine pathology while optimal visualization is
maintained. To our knowledge this is the first RCT focusing on
submucous myomas. Other studies have compared these two techniques for
the removal of endometrial polyps or placental remnants (4,5).
Trials including submucous myomas analyzed the data regarding the 4
removal of polyps and myomas as a whole (8,9). All these studies confirmed
that compared to resection, hysteroscopic morcellation is related with
shorter operating times. Moreover, there is a higher convenience of surgeons
with the technique of hysteroscopic morcellation compared with resection
(8). The ease of the technique may lower the threshold for gynecologists to
apply operative hysteroscopy.
Furthermore, if hysteroscopic myomectomy should be applied in an office

setting, operating time is the most important amongst the time variables.
Compared to bipolar resection, it appears to be more suitable for office
hysteroscopic treatment because it is fast, requires only one single insertion
and is purely mechanical. Moreover, hysteroscopic morcellation seems to
cause less pain. Smith et al. compared the TruClear™ 5.0 system (5.6 mm,
device 2.9 mm) with the VersaPoint bipolar electrosurgical system (5 fr
device) for hysteroscopic polypectomy in an office setting (10). The mean
pain score during the procedure was significantly lower for hysteroscopic
morcellation.
Contradictory with our previous RCTs using the same setup to remove polyps
and placental remnants, we observed a longer setup time in the
morcellation group (4,5). Simplifying the setup for hysteroscopic
morcellation may further reduce the time needed to perform the entire
procedure. For example, the new hand driven hysteroscopic tissue removal
system, Resectr™ (Boston Scientific, Marlborough, MA), designed for polyp
removal, replaces the electric powered control unit with food pedal by a
manually controlled handpiece. Still, connection of the vacuum tubing to
the inner blade is required. Moreover, the MyoSure MANUAL (Hologic,
Marlborough, Massachusetts, USA) is another hand driven hysteroscopic
tissue removal system designed for polyp removal in an office setting that
does not require an external vacuum tubing. Clinical trials with these novel
manual devices are ongoing (NTR7103, NTR7119).
CHAPTER 4 | 59
Conversion to resection occurred in two cases of the morcellation group in
our trial, because the myoma was too hard to be removed by the blade.
Myomas derive from smooth muscle cells making them harder than polyps
and placental remnants, and they are often calcified. Preoperative
ultrasound characteristics of the myoma (such as calcifications appearing as
echogenic foci with shadows) should be taken into account for technique
selection. Bipolar resection could be the preferred technique in the
presence of calcifications. On the other hand, myoma hardness may cause
the loop of the resectoscope to break. This specific outcome was, however,
not part of the scope of our trial.
A trend towards more incomplete myoma resections was seen in the

morcellation group. However, calcified myomas and type 2 myomas seems to
be challenging for both techniques. Although, the rates of complete removal
were still relatively high for both techniques. For hysteroscopic
morcellation, the rate of complete removal was 91 %. Rubino and Lukes
reported a mean percentage of 64 % complete myoma removal of type 0 and
1 myomas with a diameter between 1.5 and 3 cm using the 3-mm MyoSure
hysteroscopic morcellator system (11). In the bipolar resection group, the
rate of complete resection was 97 %. Retrospective data on bipolar
resection of submucous myomas demonstrated complete resection in only
78.5 %, showing that larger myomas (> 2.6 cm) with less than 65 %
protrusion in the uterine cavity are less likely to be completely resected
(12). Similarly, a prospective trial found complete removal by mono- /
bipolar resection in 73.1 % of myomas, with the size of the intramural
component as independent predictor of complete removal (OR 0.51 95 %CI
[0.28 – 0.94]) (13). Myoma diameter as independent predictor did not reach
statistical significance (OR 0.84 95 %CI [0.66–1.00]). A classification system
including size, topography, extension, penetration and wall position (STEPW
classification system) has been validated to predict complete or incomplete
resection of myomas (14). Nevertheless, partial myomectomy may also be
effective when treating abnormal uterine bleeding (15,16). Thus, additional
treatment is not always indicated in case of incomplete resection.
Three adverse events were encountered in the morcellation group (one

after conversion to resection), whereas there were none in the resection
group. In contrast, the data from the Manufacturer and User Facility Device
Experience (MAUDE) database show that in general complications such as
fluid overload, uterine perforation and bleeding do occur with hysteroscopic
morcellation, albeit less frequently compared to electrosurgical resection
(17).
Bleeding could be a concern related to the use of a hysteroscopic tissue

removal system because of the lack of electric current. In this trial, there
was no record of excessive bleeding or need for additional measures to stop
postoperative bleeding.
We did not find a difference in fluid deficit between hysteroscopic

60 | CHAPTER 4
morcellation and bipolar resection. Hysteroscopic morcellation could have
resulted in a smaller fluid deficit, as previously reported by Emanuel et al.
(9). It becomes clinically relevant when removing difficult intrauterine
pathologies such as myomas and large placental remnants. The longer the
operation time takes, the larger the fluid deficit will be, which may result in
incomplete resection or fluid overload. Our findings are in line with van
Dongen et al. (8). This may be related to the exclusion of type 2 myomas
and the fact that our trial was not powered to detect a significant
difference in secondary outcome measures.
Our RCT is the first to compare hysteroscopic morcellation with bipolar loop
resection for the removal of submucous myomas only. Similar results were
seen for both the intention-to-treat and perprotocol analysis.
Nevertheless, our trial was powered for the primary outcome of time, and
therefore no formal conclusions can be made concerning the secondary
outcomes. A second limitation of our trial is that it was an open trial, 4
although we do not expect any influence of the lack of blinding on the
primary outcome. Third, second-look hysteroscopy was not performed in all
cases, which could have caused a selection bias in our data on post-
operative adhesions. Lastly, preoperative diagnosis of type 2 myomas seems
to be challenging.
Future research focusing on hysteroscopic morcellation of myomas,

especially type 2 myomas, should be conducted. Furthermore, the
hysteroscopic morcellation devices may be further optimized to remove
(calcified) myomas. Eventually, the cost-effectiveness of hysteroscopic
morcellation for all pathologies needs to be evaluated.
CONCLUSION
Overall, there is no difference in total procedure time between

hysteroscopic morcellation using the TruClear™ system compared to bipolar
resection for the removal of smaller type 0 and 1 myomas.
Although hysteroscopic morcellation is faster, its setup time is longer.
Calcified myomas can be challenging and fluid deficit remains a limiting
factor. Optimal preoperative assessment of the myoma is key to select the
best technique.
CHAPTER 4 | 61
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and bipolar electrodes in hysteroscopic surgery. J Clin Diagn Res 2015;9(11):QC11–3.
(2) Emanuel MH. Hysteroscopy and the treatment of uterine fibroids. Best Pract Res Clin Obstet
Gynaecol 2015;29(7):920–9.
(3) Di Spiezio S, Mazzon I, Bramante S, Bettocchi S, Bifulco G, Guida M, et al. Hysteroscopic

myomectomy: a comprehensive review of surgical techniques. Hum Reprod Update 2008;14(2):101–19.
(4) Hamerlynck TWO, Van Vliet HAAM, Beerens A-S, Weyers S, Schoot BC. Hysteroscopic morcellation
versus loop resection for removal of placental remnants: a randomized trial. J Minim Invasive Gynecol
2016;23:1172–80.
(5) Hamerlynck TWO, Schoot BC, Van Vliet HAAM, Weyers S. Removal of endometrial polyps:
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2015;22(7):1237–43.
(6) Mazzon I, Favilli A, Grasso M, Horvath S, Bini V, Di Renzo GC, et al. Predicting success of single
step hysteroscopic myomectomy: a single centre large cohort study of single myomas. Int J Surg.
2015;22:10–4.
(7) Deans R, Abbott J. Review of intrauterine adhesions. J Minim Invasive Gynecol 2010;17(5):555–69.
(8) van Dongen H, Emanuel MH, Wolterbeek R, Trimbos JB, Jansen FW. Hysteroscopic morcellator for
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training. J Minim Invasive Gynecol 2008;15(4):466–71.
(9) Emanuel MH, Wamsteker K. The Intra Uterine Morcellator: a new hysteroscopic operating
technique to remove intrauterine polyps and myomas. J Minim Invasive Gynecol 2005;12(1):62–6.
(10) Smith PP, Middleton LJ, Connor M, Clark TJ. Hysteroscopic morcellation compared with electrical
resection of endometrial polyps: a randomized controlled trial. Obstet Gynecol 2014;123(4):745–51.
(11) Rubino RJ, Lukes AS. Twelve-month outcomes for patients undergoing hysteroscopic morcellation
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2015;22(2):285–90.
(12) Keltz MD, Greene AD, Morrissey MB, Vega M, Moshier E. Sonohysterographic predictors of
successful hysteroscopic myomectomies. J Soc Laparoendosc Surg. 2015;19(1).
(13) Mavrelos D, Naftalin J, Hoo W, Ben-Nagi J, Holland T, Jurkovic D. Preoperative assessment of

submucous fibroids by three-dimensional saline contrast sonohysterography. Ultrasound Obstet
Gynecol 2011;38(3):350–4.
(14) Lasmar RB, Lasmar BP, Celeste RK, da Rosa DB, de B.Depes D, et al. A new system to classify
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(15) Dueholm M, Forman A, Ingerslev J. Regression of residual tissue after incomplete resection of
submucous myomas. Gynaecol Endosc. 1998;7(6):309–14.
(16) Van Dongen H, Emanuel MH, Smeets MJ, Trimbos B, Jansen FW. Follow-u after incomplete
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62 | CHAPTER 4
4
CHAPTER 4 | 63
CHAPTER 5
Manual morcellation (Resectr™ 9fr) versus
electromechanical morcellation (Truclear™)
for hysteroscopic polypectomy:
a randomized controlled non-inferiority trial
Steffi van Wessel

Tjalina Hamerlynck
Hubertus van Vliet
Benedictus Schoot
Steven Weyers
Acta Obstet Gynecol Scand. 2023;102:209-217

ABSTRACT
Introduction Meta-analyses comparing hysteroscopic electromechanical

morcellation with electrosurgical resection showed a shorter operating time
for electromechanical morcellation, mainly for polypectomy. The Resectr™
9fr is a new hysteroscopic manual morcellator, designed to simplify this
procedure. We aimed to compare manual with electromechanical
morcellation for hysteroscopic polypectomy.
Material and methods This two-center randomized controlled non-

inferiority trial was performed from 2018 to 2021 in the Catharina Hospital
(Eindhoven, the Netherlands) and the Ghent University Hospital (Ghent,
Belgium). The study was registered at the Dutch Trial Register (NL6922)
(https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7118). One hundred
forty women with polyps (≥ 8 - ≤ 20mm) scheduled for hysteroscopic
removal were randomized between manual (Resectr™ 9fr.) or electro-
mechanical (Truclear™) morcellation. The primary outcome is time
(instrumentation setup, resection and total procedure time).
Results The non-inferiority margin for the primary outcome time was 1.3.
Mean instrumentation setup time was 10% shorter with the manual (M)
compared to the electromechanical (E) morcellator (estimated mean ratio
manual/electromechanical = 0.9; 97.5% Confidence interval (CI) 0.8 - 1.1).
Mean resection time was 30% longer with the manual compared to the motor
driven system (estimated mean ratio manual/electromechanical = 1.3;
97.5% CI 0.9 – 1.9). Mean total procedure time was 10% longer with the
manual compared to the electromechanical morcellator (estimated mean
ratio manual/electromechanical = 1.1; 95% CI 0.91 - 1.298). The estimated
odds (electromechanical/manual) of a better surgeon’s safety, effective
and comfort score were, respectively, 4.5 (95% CI 0.9 - 22.1), 7.0 (95%CI
1.5 – 31.9), and 5.9 (95%CI 1.1 – 30.3) times higher with the motor driven
compared to manual driven morcellator. Conversion rates and incomplete
resection rates were comparable in both groups (manual versus electro-
mechanical) (7.6% (4/66) versus 2.9% (2/68) and 6.1% (4/66) vs 3.0% (2/66),
respectively). No intra- and postoperative complications were registered.
Conclusion The manual morcellator was non-inferior to the electro-

mechanical morcellator for hysteroscopic polypectomy in terms of mean
instrumentation setup time and total procedure time. Results on resection
time were inconclusive. Conversion and incomplete resection rates were
within the range reported in the literature. Surgeon’s reported rating for
both devices was high, however, in favor of the motor driven tissue removal
system.
66 | CHAPTER 5
INTRODUCTION
The hysteroscopic electromechanical morcellator was introduced to

facilitate the removal of intrauterine pathology: an optimal view and fewer
complications (uterine perforation, gas embolism and thermal damage) and
shorter learning curve (1,2). Different systems have been designed
(Truclear™ (Medtronic, Minneapolis, USA), MyoSure (Hologic inc.,
Marlborough, USA) and Intrauterine BIGATTI Shaver® (IBS)(Karl Storz,
Tuttlingen, Germany)).
Three meta-analyses have been performed to compare the hysteroscopic

electromechanical morcellator with electrosurgical resection for the
removal of polyps and type 0 and 1 myomas (3–5). Subgroup analysis of data
derived from randomized controlled trials (RCTs) revealed a significantly
shorter operating time for hysteroscopic electromechanical morcellation
(mean difference (MD) 4.5 minutes). Subgroup analysis per pathology
however showed only a benefit for the removal of polyps (MD 7.8 minutes).
Overall, the complete removal rate was in favor of the hysteroscopic
electromechanical morcellator, whereas the complication rate was not
significantly different.
However, the development of devices continued and a new hysteroscopic

5
manual morcellator, Resectr™ 9fr. (Minerva Surgical St Clara CA), was CE
(Conformité Européene) marked in 2016 and FDA (Food and Drug
Administration) approved in 2020. Its potential benefits are a simplified
setup, because of the replacement of the electrically powered control by a
simple handgrip, and a larger working window (7.5 mm).
The aim of this RCT was to compare the manual morcellator (Resectr™ 9fr.)
with the electromechanical morcellator (Truclear™) for hysteroscopic
polypectomy in terms of procedure time, surgeon’s convenience, safety,
complications, conversion rate and completeness of removal.
MATERIAL AND METHODS
This two-center, single-blinded RCT was performed from September 2018 to

August 2021 in the Catharina Hospital (Eindhoven, the Netherlands) and the
Ghent University Hospital (Ghent, Belgium). Written informed consent was
obtained from all participants.
Women with endometrial polyps (largest diameter ≥ 8 - ≤ 20mm) scheduled

for hysteroscopic removal were eligible to participate. Diagnosis was made
by transvaginal ultrasound, saline infusion sonography (SIS) and/or
diagnostic hysteroscopy. Exclusion criteria were polyps with the largest
diameter smaller than 8mm or larger than 20mm, myomas, visual or
pathological evidence for malignancy, untreated cervical stenosis or the
CHAPTER 5 | 67
presence of any contraindication for operative hysteroscopy.
After written informed consent, women were randomly assigned in a 1:1

ratio to manual or electromechanical morcellation. A computer-generated
random allocation sequence (Research manager) was used, with a block size
of 6. Randomization was stratified by center and polyp size (≥ 8mm -
< 15mm or ≥ 15mm - ≤ 20mm). Women were unaware of the treatment
allocation. The Consolidated Standards of Reporting Trials 2010 statement
for reporting of a RCT was followed.
Hysteroscopic polypectomy was performed in day surgery or office setting,

according to local practices. Different types of anesthesia were used (none,
cervical block, conscious sedation or spinal or general anesthesia).
No cervical ripening agents or antibiotic prophylaxis were used.
All procedures were done using the Truclear™ 5C hysteroscope (5.6mm,
17fr.), normal saline for distention and irrigation of the uterine cavity, and
Hegar dilators up to 6mm for cervical dilation if necessary. Fluid balance
was closely monitored using the Hysteroscopic Fluid Management System
(Medtronic, Minneapolis, MN, USA; maximum pressure setting of 120 mmHg
and maximum flow setting of 700 mL/min).
The Resectr™ 9fr. (3mm) was used in the intervention group (Figure 1). This
new hand driven tissue removal device consists of a 35cm long cannula,
with a 7.5mm cutting window and an internal rotating blade in an outer
tube. The hand activation of the Resectr™ 9fr. replaces the electrically
powered control unit in the existing motor driven devices. Each squeeze in
the handpiece initiates 6 turning movements of the inner blade. During each
turn, the inner blade can cut tissue. The ENDOMAT® SELECT (Karl Storz,
Tuttlingen, Germany; maximum flow setting of 300 mL/min), activated by a
foot pedal, was used for controlled suction of the resected tissue, which is
aspirated through the hollow lumen of the tissue removal device, collected
in a pouch and available for pathology analysis. When the rotating inner
blade and the ENDOMAT® SELECT are not activated, the window opening of
the Resectr™ 9fr. is always closed to prevent fluid loss and loss of distension.
The Truclear™ incisor mini device (3 mm, 9fr.), currently renamed as soft
tissue shaver mini device, was used in the control group. The system has a
5 mm cutting window. The technique of hysteroscopic electromechanical
morcellation has been described previously (1).
The surgeons, experienced in operative hysteroscopy, had in vitro training.
The primary outcomes were instrumentation setup time and resection

time. The instrumentation setup time was defined as the time to set up the
hysteroscopic instrumentation ready for use, it included cervical dilation (if
necessary), assembly of the hysteroscopic morcellator, and was defined as
ending when the hysteroscope was ready to be inserted. The resection time
included only the removal of the largest polyp. Registration started when
68 | CHAPTER 5
the hysteroscope was introduced through the external cervical ostium until
the time at which the largest polyp was completely removed.
Secondary outcomes were total procedure time (the sum of the

instrumentation setup and resection time), fluid deficit, number of
insertions, subjective surgeon reported outcomes on a 5-point Likert scale
immediately after the hysteroscopic procedure (safety (how safe did you
feel with the instrument?), effective (How effective did you find the
instrument to resect polyp tissue?) and comfort (how comfortable did you
find the instrument?) scores), intra- and postoperative complications
(including fluid deficit ≥ 2500 mL with clinical consequences, blood loss
(> 500mL), uterine perforation and infection), conversion rate (an
interruption of the hysteroscopic procedure to switch to another
procedure or another device in order to complete the surgery),
completeness of removal (removal of all visible polyp tissue from the
uterine cavity), short-term effectiveness (persistence of symptoms at 6
weeks follow-up), patient’s satisfaction with the procedure on a 5-point
Likert scale (at 6 weeks follow-up), postoperative availability of tissue for
pathology analysis and pathology diagnosis.
Figure 1 Resectr™ 9fr device

5
(Reprinted with permission of dr. Skalnyi (Minerva Surgical))
Statistical analyses
The sample size was calculated to test for non-inferiority of the
hysteroscopic manual morcellator compared to the electromechanical
system with respect to the geometric mean instrumentation setup and
resection times. In the paper of Hamerlynck et al, the mean
instrumentation setup and resection times with the electromechanical
morcellator were 7.3 minutes (+/- standard deviation (SD) 2.5 minutes) and
6.6 minutes (+/- SD 3.3 minutes), corresponding to coefficients of variation
of 0.3 and 0.5 respectively (6). A mean ratio of 1.3 as non-inferiority margin
CHAPTER 5 | 69
for the manual versus electromechanical morcellator was chosen and would
imply upper limits for mean instrumentation setup and resection times
with the manual morcellator of 9.5 minutes and 8.6 minutes, respectively.
A non-inferiority test of lognormal geometric means using the confidence
interval (CI) approach (97.5% CI constructed) on data from a balanced
parallel-group design with sample sizes of 63 women in each group (126
women in total), will achieve at least 80% power when the true geometric
mean ratio is 1, the common coefficient of variation is 0.5, and the non-
inferiority limit is 1.3. To account for 10% drop-out, this sample size was
increased to 140 women in total. The sample size was calculated in R
version 4.1.1 using the “PowerTOST” package. Testing for superiority after
non-inferiority can be demonstrated and will not impact the type I error
rate, nor the sample size.
Data were collected and analyzed using the statistical program SPSS (version
27.0, IBM Corp., Armonk, NY). Continuous variables were summarized with
descriptive statistics (mean and SD for data that were normally distributed,
geometric mean and geometric SD factor for instrumentation setup,
resection and total procedure times, and median and interquartile range
(IQR) otherwise). Categorical data were presented as absolute frequencies
and percentages.
Linear mixed models of log-transformed instrumentation setup, resection,
and total procedure times on randomization group and stratification group
were fitted with a random intercept for surgeon. The upper limit of the
confidence interval for the geometric mean ratio will be compared with the
predefined non-inferiority margin of 1.3. Generalized estimating equations
models with exchangeable working correlation matrix for women within
surgeons were fitted for the ordinal 5-point Likert scales for safety,
effective and comfort scores (cumulative logit). Analyses for conversion rate
and complete resection rate were kept descriptive because of quasi
complete separation.
For the two primary endpoints 97.5% CI are reported. Comparisons of other
endpoints were not adjusted for multiple testing (95% CIs are reported),
because these analyses will only be interpreted if first non-inferiority on one
of the primary endpoints can be demonstrated.
An intention-to-treat analysis was performed. A per protocol analysis was

also performed to assess the robustness of our findings, excluding women
that did not receive the allocated treatment, had too large polyps (> 20mm)
or had a conversion.
Ethical approval
Approval was obtained from both ethical committees (date of approval
Belgium 09/01/2018). The study was registered on March 27th 2018 at the
Dutch Trial Register (NL6922). However, this database is currently
unavailable and registered studies were moved to the International Clinical
Trial Registry Platform (ICTRP) (https://trialsearch.who.int/Trial2.aspx?Tri-
70 | CHAPTER 5
alID=NTR7118). Participant enrollment started in September 2018.
RESULTS
After informed consent, 140 women were randomized. A flowchart can be

found in Figure 2. Forty-six percent (65/140) were treated in the
Catharina Hospital and 54% (75/140) in the Ghent University Hospital.
There was 1 drop out in each group. In the manual morcellation group, 1
woman was diagnosed with breast cancer and the hysteroscopic
polypectomy, using a bipolar resectoscope, was performed concomitant
with the breast surgery. In the electromechanical morcellation group, the
procedure was cancelled in 1 woman. There were 2 withdrawals of consent
in the manual morcellation group. One for no specific reason, and the other
because there would be no compensation in case of complications. In the
manual morcellation group, the pathology was intraoperatively diagnosed as
a myoma, the intervention was rescheduled as a procedure under conscious
sedation.
Figure 2 CONSORT flowchart

5
Allocation
Follow-up
Analyses
Patient demographics and polyp characteristics are shown in Table 1 and 2,

respectively. The estimated geometric mean instrumentation setup time was
10% shorter with the manual morcellator compared to the electro-
mechanical tissue system (estimated mean ratio manual/electro-
CHAPTER 5 | 71
mechanical = 0.9; 97.5% CI 0.8 - 1.1). The upper limit of the 97.5% CI falls
below the pre-defined non-inferiority limit of 1.3, hence we can conclude
that the manual morcellator is non-inferior to the electromechanical
morcellator with respect to the geometric mean instrumentation setup time
(3.3 minutes (1.2) versus 3.3 minutes (1.2)). Superiority however could not
be demonstrated (p = 0.13).
The estimated geometric mean resection time was 30% longer with the
manual morcellator compared to the electromechanincal morcellator
(Estimated mean ratio manual/electromechanical = 1.3; 97.5% CI 0.9 – 1.9).
The upper limit of the 97.5% CI falls above the pre-defined non-inferiority
limit of 1.3, hence we are inconclusive about clinical non-inferiority of the
manual morcellator compared to the electromechanical morcellator, with
respect to the geometric mean resection time (3.7 minutes (1.2) versus 2.7
minute (1.2)).
The estimated geometric mean total procedure time was 10% longer with
the manual morcellator compared to the electromechanical morcellator
(Estimated mean ratio manual/electromechanical = 1.1; 95% CI 0.91 -
1.298). We can conclude that the manual morcellation is non-inferior to
electromechanical morcellation, with respect to the geometric mean total
procedure time (8.2 minutes (3.7) versus 7.4 minutes (3.7)). Superiority
however could not be demonstrated (p = 0.37).
The per protocol analysis led to similar conclusions.
Table 1 Patient demographics
72 | CHAPTER 5
Table 2 Polyp characteristics
Operative data are presented in Table 3. A congenital uterine malformation

was present in 2 cases of the hand driven tissue removal system group (class
U2 (partial septate uterus) and class 3Bb (complete bicorporal uterus)).
A myoma was visualized in 4 cases of the manual morcellation group
(concomitant to a polyp and left in situ (n=2), intraoperatively diagnosed
instead of a polyp and resected (n=1) and intraoperatively diagnosed instead
of a polyp and rescheduled for removal (n=1)) and in 2 cases of the electro-
mechanical group (intraoperatively diagnosed instead of a polyp and
resected (n=2)).
The conversion rate was 7.6% (5/66) and 2.9% (2/68) in the manual and
electromechnical morcellation l group, respectively. In 2 cases the Resectr™
9fr was converted to the resectoscope because of the intraoperative
diagnosis of a myoma (n=1) and in order to obtain a complete resection
of hard tissue that turned out to be a myoma (n=1). The Resectr™ 9fr was
converted to the Truclear™ incisor mini device because of device deficiency
(defective inner blade n=1), a large polyp (n=1) and poor visibility due to
blood loss (n=1). Because of the intraoperative diagnosis of a myoma, the
CHAPTER 5 | 73
Truclear™ incisor mini device was converted to the resectoscope (n=1) and
to the Truclear™ ultra mini device, currently renamed as dense tissue shaver
mini device (n=1).
Polyp resection was incomplete in 6.1% (4/66) of the cases in the

manual morcellator group (intraoperative diagnosis of a myoma (n=1),
fundal position (n=2) and conversion to the resectoscope in order to obtain
complete resection of hard tissue that turned out to be a myoma (n=1)).
In the electromechanical morcellation group, incomplete resection occurred
in 3.0% (2/66) of the cases (intraoperative myoma diagnosis (n=1) and fundal
position (n=1)).
No complications were recorded and tissue was available for pathology

analyses in all cases. It was necessary to reinsert the Resectr™ 9fr. once (the
tissue was stuck in the working window (n=1).
The estimated odds of a better surgeon’s safety, effective and comfort score
(above any fixed level) were, respectively, 4.5 ((95% CI 0.9 - 22.1),
P = 0.06), 7.0 ((95%CI 1.5 – 31.9), P = 0.01) and 5.9 ((95%CI 1.1 – 30.3),
P = 0.03) times higher with the electromechanical morcellator than with the
manual morcellator.
Table 3 Operative data
74 | CHAPTER 5
The postoperative data are presented in Table 4. An unscheduled post-
operative visit with the gynecologist was recorded in 1.5% (1/66) of the
manual morcellation group (pathology analyses revealed a carcinoma (n=1))
and in 4.4% (3/68) of the electromechanical group (bleeding and abdominal
pain (n=3)). An unscheduled postoperative visit with the general practitioner
was recorded in 1.5% (1/66) of the manual morcellation group (abdominal
pain (n=1)) and 4.4% (3/68) of the electromechanical morcellation group
(abdominal pain and fever (n=1), flu like symptoms (n=1) and gastritis
(n=1)).
Tissue was insufficient for pathology analysis in 1.5% (1/68) of the electro-
mechanical morcellator group.
Table 4 Postoperative data
CHAPTER 5 | 75
DISCUSSION
The manual morcellator (Resectr™ 9fr.) was non-inferior to the electro-

mechanical morcellator (Truclear™) in terms of mean instrumentation setup
and total procedure time. Our results were inconclusive regarding polyp
resection time. Overall, instrumentation setup-, resection- and total
procedure times for hysteroscopic polypectomy with both tissue removal
systems were short.
To our knowledge, our RCT is the first to report on the clinical use of a new
manual morcellator for hysteroscopic polypectomy and to compare this
technique with electromechanical removal. We used unambiguous time
definitions. Moreover, groups were comparable by measuring only the
resection time of the largest polyp and by the stratified randomization.
Our trial has some limitations. The surgeon reported outcomes are
subjective, however, the trial was multicentric and different surgeons were
involved. We did not analyze the cost-effectiveness. Nevertheless, since the
procedure time and the hospitalization are similar, the difference between
the two techniques can be based on the device and sterilization costs.
Furthermore, the polyp size was limited to 2 cm in our trial, but in the
existing literature it is rarely larger. Unfortunately, the primary outcome
was missing in some cases, but this was less than 10%.
The simplified setup of the Resectr™ 9fr. was non-inferior to the

Truclear™ incisor mini device regarding mean instrumentation setup time,
but we could not demonstrate its superiority. Replacement of the
ENDOMAT® SELECT pump by a vacuum wall source, or an integrated vacuum
system could further simplify the setup. The reported instrumentation setup
times associated with motor driven hysteroscopic tissue removal systems
(median 5.2 minutes) were higher (7).
The Resectr™ 9fr. is equipped with a larger working window (7.5 mm) than
the Truclear™ incisor mini device (5 mm). This could have resulted in shorter
resection times. Our results were inconclusive regarding non-inferiority and
the mean resection time was shorter for the electromechanical morcellator.
This might be explained by the inconsistent activation of the hand piece,
resulting in variable resection speeds. Notwithstanding, the resection times
were low. The reported resection times of electromechanical morcellators
were not comparable to our measures because of heterogeneity in terms of
polyp size and number (8,9).
We could not observe a difference in conversion rates and incomplete

resection rates between the two techniques in our sample but the study was
not powered on these outcomes. The main reason for conversion to another
technique in both groups was the presence of a myoma, which consists of
dense tissue. The presence of a myoma and a fundal polyp were the main
76 | CHAPTER 5
reasons for incomplete resection in both groups. The Resectr™ 9fr. was not
designed to remove myomas. The Truclear™ tissue removal system has
specific devices developed for dense tissue (ultra mini and ultra plus
devices). Fundal polyps may be hard to reach. The only two RCTs using the
Truclear™ incisor mini device for hysteroscopic polypectomy did not report
on conversion rates Their incomplete resection rates ranged from 2% to 8%
and was mainly a result of inability to access the intrauterine cavity.
Manual morcellation was associated with higher fluid deficits than the
electromechanical system for hysteroscopic polypectomy. Overall, these
deficits were low and the maximum fluid deficit was 1620ml. Smith et al and
Pampalona et al did not calculate their fluid deficit (8,9).
Surgeon’s safety, effective and comfort scores were in favor of the electro-
mechanical morcellator. Overall, these scores were high so one can
question its clinical relevance. Surgeon’s subjective scores were only
reported by Tsuchiya et al, using the Truclear™ incisor plus device for polyp
removal (10). Maneuverability was scored on a Visual Analogue Scale (VAS)
and was 7.7.
A difference in patient’s satisfaction score could not be demonstrated. This

was not yet reported before. 5
Tissue was insufficient for pathology analysis in 1 case of the motor driven
group. The Truclear™ tubing is long and it is necessary to flush it sufficiently
in order to remove all the tissue. When removing small intrauterine
pathologies, the resection time is brief, so we need to be aware that
sufficient flushing does not automatically happen during the procedure.
Apart from this, it has been shown that the Truclear™ tissue removal system
provides an adequate specimen for pathology analysis (11).
To our knowledge, there is only one other hysteroscopic manual morcellator,

the MyoSure Manual (Hologic inc.,Marlborough, USA), which was CE marked
in 2018. However, there are no studies available.
Future research should focus on the cost-effectiveness of hysteroscopic

morcellators in general, the optimalisation of the manual device (adaption
of the device tip to reach the fundal region, an integrated vacuum system
and a non-disposable variant) and other indications (smaller placental
remnants).
CONCLUSION
In our trial, the manual morcellator was non-inferior to the electro-

mechanical morcellator for hysteroscopic polypectomy in terms of mean
instrumentation setup and total procedure time. Results on resection time
CHAPTER 5 | 77
were inconclusive. Conversion and incomplete resection rates were within
the range reported in the literature. Surgeon’s reported outcomes were
high, but in favor of the electromechanical morcellator. Women were
satisfied with both techniques.
78 | CHAPTER 5
REFERENCES
(1) Emanuel MH, Wamsteker K. The Intra Uterine Morcellator: A new hysteroscopic operating
technique to remove intrauterine polyps and myomas. J Minim Invasive Gynecol. 2005;12(1):62–6.
(2) van Dongen H, Emanuel MH, Wolterbeek R, Trimbos JB, Jansen FW. Hysteroscopic Morcellator for
Removal of Intrauterine Polyps and Myomas: A Randomized Controlled Pilot Study among Residents in
Training. J Minim Invasive Gynecol. 2008;15(4):466–71.
(3) Shazly SAM, Laughlin-Tommaso SK, Breitkopf DM, Hopkins MR, Burnett TL, Green IC, et al.
Hysteroscopic Morcellation Versus Resection for the Treatment of Uterine Cavitary Lesions: A
Systematic Review and Meta-analysis. J Minim Invasive Gynecol. 2016;23(6):867–77.
(4) Yin X, Cheng J, Ansari SH, Campo R, Di W, Li W, et al. Hysteroscopic tissue removal systems for the
treatment of intrauterine pathology: a systematic review and meta-analysis. Facts, views Vis ObGyn.
2018;10(4):207–13.
(5) Li C, Dai Z, Gong Y, Xie B, Wang B. A systematic review and meta-analysis of randomized
controlled trials comparing hysteroscopic morcellation with resectoscopy for patients with
endometrial lesions. Int J Gynecol Obstet. 2017;136(1):6–12.
(6) Hamerlynck TWO, Dietz V, Schoot BC. Clinical implementation of the hysteroscopic morcellator
for removal of intrauterine myomas and polyps. A retrospective descriptive study. Gynecol Surg.
2011;8(2):193–6.
Hysteroscopic morcellation versus bipolar resectoscopy, a randomized trial. J Minim Invasive Gynecol.
2015;22(7):1237–43. 5
(8) Pampalona JR, Bastos MD, Moreno GM, Pust AB, Montesdeoca GE, Guerra Garcia A, et al.
A Comparison of Hysteroscopic Mechanical Tissue Removal With Bipolar Electrical Resection for the
Management of Endometrial Polyps in an Ambulatory Care Setting: Preliminary Results. J Minim
Invasive Gynecol. 2015;22(3):440–5.
resection of endometrial polyps: A randomized controlled trial. Obstet Gynecol. 2014;123(4):745–51.
(10) Tsuchiya A, Komatsu Y, Matsuyama R, Tsuchiya H, Takemura Y, Nishii O. Intraoperative and

postoperative clinical evaluation of the hysteroscopic morcellator system for endometrial
polypectomy: A prospective, randomized, single-blind, parallel group comparison study. Gynecol
Minim Invasive Ther. 2018;7(1):16–21.
(11) Franchini M, Zolfanelli F, Gallorini M, Giarrè G, Fimiani R, Florio P. Hysteroscopic polypectomy in

an office setting: Specimen quality assessment for histopathological evaluation. Eur J Obstet Gynecol
Reprod Biol. 2015;189:64–7.
CHAPTER 5 | 79
CHAPTER 6
Clinical evaluation of a new hand driven
hysteroscopic tissue removal device,
Resectr™ 5fr, for the resection of
endometrial polyps in an office setting
Steffi van Wessel

Tjalina Hamerlynck
Hubertus van Vliet
Steven Weyers
Benedictus Schoot

ABSTRACT
Purpose A first clinical evaluation of a new hand driven hysteroscopic tissue

removal device, Resectr™ 5fr, for office polypectomy without any
anesthesia.
Methods Women with at least one small endometrial polyp were eligible.
Hysteroscopic polypectomy was performed using the Resectr™ 5fr in an
office setting, without any anesthesia.
Results One hundred and two hysteroscopic polypectomies were included in

the analysis. The median installation time was 1.9 minutes (95% confidence
interval (CI) 1.6 - 2.1). The median time to complete polyp removal was
1.2 minutes (95%CI 0.8 – 1.6). The median surgeon’s safety, practical and
comfort scores on a 5-point Likert scale were high (5 (5-5), 5 (4-5) and 5 (4-
5), respectively). Women’s pain score was low (median 1 (0-3)), whereas the
satisfaction rate was high (median 5 (5-5)), both on a 5-point Likert scale.
There were two conversions (hysteroscopic scissors (n=1), a new Resectr™
5fr device (n=1)). There was one incomplete procedure (tissue hardness).
Conclusion Hysteroscopic removal of small polyps, using the Resectr™ 5fr

in an office setting is feasible in terms of installation and resection time.
Surgeon’s practical, comfort, and safety scores are high, whereas women
report low pain scores and high satisfaction rates.
82 | CHAPTER 6
INTRODUCTION
Endometrial polyps are focal outgrowths containing glands, stroma and

blood vessels.(1) The most prevalent symptom is abnormal uterine
bleeding (AUB) occurring in up to 68% of cases.(2) Their presence has also
been linked with female infertility.(3) Nevertheless, they can be
asymptomatic.(4) Although endometrial polyps are benign, pre- and
malignant transformation may occur in around 3.4%.(5) Hysteroscopic
polypectomy is recommended in case of symptoms.(3,6–9) The management
in asymptomatic women is debatable.(9–11)
Miniaturization of hysteroscopes and its instruments enabled hysteroscopic

polypectomy to be performed in an office setting. The first instruments used
for office hysteroscopic polypectomy were 5fr mechanical instruments
(scissor and grasper), later expanded with 5fr bipolar instruments.(12)
These are fragile and have a limited degree of movement. The main
restriction is the ratio between the polyp size and the diameter of the
internal cervical ostium, which is associated with additional maneuvers for
tissue extraction, longer operating times, and higher pain scores.(13–15)
Mechanical hysteroscopic tissue removal systems offer a solution by their
simultaneous cutting and aspiration effect. Compared to 5fr bipolar
instruments, a mechanical hysteroscopic tissue removal system is
significantly faster, more acceptable, and successful. (16,17)
However, the development of devices continued and a small, hand driven

tissue removal system, Resectr™ 5fr. (1.66mm) (Minerva Surgical, Santa
Clara CA), which was CE marked in 2016 and FDA approved in 2020, was
launched to perform office hysteroscopic polypectomy. Its benefits are that
6
the electrically powered control unit is replaced by a simple hand grip,
which simplifies the setup, and that it fits through a 5fr. working channel.
The aim of the current trial was to perform a first clinical evaluation, in
accordance with the IDEAL framework, of the device for office polypectomy.
METHODS
This multicenter, prospective cohort study was conducted at the Catharina

Hospital (Eindhoven, the Netherlands) and the Ghent University
Hospital (Ghent, Belgium) from October 2018 until March 2021. The study
was approved by the ethical committees of both centers and it was
registered at the Dutch Clinical Trial Registry (NL6923). Written informed
consent was obtained from all women.
Women were eligible to participate when they had at least one small (mean
diameter ≤ 8 mm) endometrial polyp, scheduled for hysteroscopic removal.
Diagnosis was made by transvaginal ultrasound, saline infusion sonography
(SIS) and/or diagnostic hysteroscopy. Exclusion criteria were endometrial
CHAPTER 6 | 83
polyps with a mean diameter larger than 8 mm, evidence of malignancy,
untreated cervical stenosis, or the presence of a contraindication for
operative hysteroscopy.
Hysteroscopic polypectomy was performed in an office setting without any

anesthesia. The procedure was done immediately after diagnosis (‘see and
treat’) or scheduled according to local circumstances and patient’s
preference. Women were allowed to take oral analgesia according to local
practices (no standard protocol at the Ghent University Hospital, non-
steroidal anti-inflammatory drug (NSAID) (Naproxen® 500mg) the night
before the procedure at the Catharina Hospital). The vaginoscopic approach
was used without cervical preparation. Normal saline, warmed to 37.0°C,
was used as distention medium and delivered by a pressure bag or the
ENDOFLOW®II Warming, Irrigation and Suction system (Rocamed).
No antibiotic prophylaxis was administered.
Polyp removal was performed using the Resectr™ 5fr. a new hand driven
tissue removal device, consisting of a 35 cm long cannula and, a 5 mm
working window and an internal rotating blade in an outer tube (Figure 1).
The device was introduced into the uterine cavity through the 5fr. working
channel of pre-existing small diameter hysteroscope (≤ 15fr, ≤ 5mm). The
hand activation of the Resectr™ 5fr. replaces the electric powered control
unit in the existing motor driven devices. Each squeeze in the handpiece
initiates six turning movements of the inner blade (3 rotations clockwise,
followed by 3 rotations counterclockwise). During each turn, the inner blade
can cut tissue. The ENDOMAT® SELECT (Karl Storz, Tuttlingen, Germany;
maximum flow setting of 300 mL/min), activated by a foot pedal, was used
for controlled suction of the resected tissue, which is aspirated through the
hollow lumen of the tissue removal device, collected in a pouch and
available for pathology analysis. When the rotating inner blade and the
ENDOMAT® SELECT are not activated, the window opening of the Resectr™
5fr. is always closed to prevent fluid loss and uterine cavity collapse.
Figure 1 Resectr™ 5fr device
84 | CHAPTER 6
The procedures were done by four experienced hysteroscopic surgeons after
in vitro training.
Women were scheduled for a postoperative visit (telephone or physical) 6

weeks after the operative hysteroscopy.
The primary outcomes are the installation and resection times. Installation
time was defined as the time to set up the hysteroscopic instrumentation
ready for use at the back table (assembling the hysteroscope by connecting
camera light cable and irrigation system, connecting the ENDOMAT® SELECT
tubing to the Resectr™ 5fr and insertion of the device in the 5fr working
channel). Resection time was defined as the time from first instrument
activation until complete removal of the largest polyp.
The secondary outcomes were the surgeon’s practical, comfort and safety
scores on a 5-point Likert scale, patient’s pain (after the procedure) and
satisfaction scores (at 6 weeks follow-up) (5-point Likert scale), conversion
rates (an interruption of the hysteroscopic procedure to switch to another
procedure or another device in order to complete the surgery),
completeness of removal (extraction of all polyp tissue from the uterine
cavity), intra- and postoperative complications (including fluid deficit
≥ 2500mL with clinical consequences, hemorrhage (> 500mL), uterine
perforation, infection), short-term effectiveness (persistence of symptoms
at 6 weeks follow-up), postoperative availability of tissue for pathology
analysis and pathology diagnosis.
The intended sample size was set at 100 procedures.

6
Statistical analyses
Data was collected and analyzed using the statistical program SPSS
(version 27.0, IBM Corp., Armonk, NY). Continuous variables were
summarized with descriptive statistics (mean and standard deviation for
data normally distributed and median and interquartile range (IQR)
otherwise). Categorical data was presented as frequency and percentage.
Kaplan-Meier estimates for time to installation and time to complete polyp
removal were plotted with the log-log 95% confidence interval (CI).
The median time to installation is the earliest time at which at least 50% of
the installations were accomplished. The median time to complete polyp
removal is the earliest time at which at least 50% of the polyps were
completely removed. The value for the variable of interest is used
regardless of whether or not the intercurrent event occurs (treatment policy
strategy). Correlation between 2 variables was evaluated with Spearman’s
correlation. Numerical data was analyzed using the Mann-Whitney U test
and Kruskal Wallis test to compare 2 or more than 2 groups. Categorical
data was analyzed using the Chi-square test. It concerns post-hoc analyses
that were not predefined. Level of significance was set at P < .05.
CHAPTER 6 | 85
RESULTS
One hundred and twelve women were enrolled in the study (Figure 2).
Conscious sedation and general anesthesia were performed in one and five
cases respectively, because of patient’s preference or a painful diagnostic
hysteroscopy after inclusion. Finally, 102 hysteroscopic polypectomies, using
the Resectr™ 5fr in an office setting without any anesthesia, were included
in the analysis.
Figure 2 Patient enrollment
Patient demographics and polyp characteristics are shown in Table 1 and 2,

respectively. One woman had an ASA III score because of a previous kidney
transplant.
Surgery data is summarized in Table 3. The time to installation curve and

the time to complete polyp resection curve are shown in Figure 3 and 4,
86 | CHAPTER 6
respectively. The median installation time was 1.9 minutes (95%CI 1.6 - 2.1).
The median time to complete polyp removal was 1.2 minutes (95%CI 0.8
– 1.6). There was no significant difference in resection times amongst the
four surgeons (P = .21). The surgeon’s practical and comfort scores were
negatively correlated with resection times (P < .001). Sixty-six percent of
the women took pain medication within a time frame from the night before
until the morning of the procedure (paracetamol 500mg (n=2), paracetamol
1000mg (n=9), paracetamol + codeine (n=1), paracetamol + NSAID (n=2),
NSAID (n=53)). Pain scores were overall very low, and women who took pain
medication reported significantly lower pain scores (P = .009). A significant
correlation between patient’s pain score and resection time could not be
found (P = .09).
Table 1 Patient demographics
CHAPTER 6 | 87
Table 2 Polyp characteristics
One hysteroscopic procedure was discontinued because the polyp tissue

located at the posterior wall was too hard, with the inability to remove the
base. Tissue hardness suggested the presence of a myoma. The resection
time was 7.4 minutes with a fluid deficit of 300mL. The woman was
rescheduled for a hysteroscopic polypectomy using the resectoscope in an
inpatient setting. This procedure was uneventful and pathology analysis
confirmed the presence of a polyp. In two cases the Resectr™ device became
nonfunctional. In one case the hand piece became unusable and the device
was converted to hysteroscopic scissors in order to completely remove a
polyp located at the posterior wall. The resection time was 7.1 minutes.
Fluid deficit was not recorded. Pathology analysis confirmed the presence of
a polyp. In the other case the Resectr™ device had a defective inner blade.
88 | CHAPTER 6
Table 3 Surgery data
6
Figure 3 Time to installation curve
CHAPTER 6 | 89
Figure 4 Time to complete polyp resection curve
With a new device, the polyp, located at the posterior wall, was removed
completely without complications. The resection time was 5.4 minutes with
a fluid deficit of 50 mL. Polyp tissue was confirmed on pathology analysis.
Tissue was not available for pathology analysis in one case because of a
small amount of tissue, but non-malignant polyp tissue was already
confirmed on biopsy during the diagnostic phase.
No intraoperative complications were recorded.
Postoperative data are shown in Table 4. Eleven percent still complained

of blood loss and/or pain. New symptoms were reported in 3% (blood loss
(n=1), pain (n=1), dysmenorrhea (n=1)). Polyps were confirmed in 88%.
One woman contacted her gynecologist earlier than the planned post-
operative visit because of blood loss. The polyp was located at the
posterior wall and resected in 0.9 minutes. An intrauterine device was
placed at the time of the surgery, but it was expulsed after 1 month.
This patient was already known with heavy menstrual bleeding. She was
admitted for 2 nights and received packed cells because of a hemoglobin
drop to 7.4 mg/dL. She was treated with NSAIDS, oral progestogens and
tranexamic acid, but eventually a hysterectomy was performed. Two women
contacted their general practitioner before the planned postoperative visit
(pyrosis (n=1), tiredness (n=1)).
90 | CHAPTER 6
Table 4 Postoperative data
DISCUSSION
Hysteroscopic polypectomy in an office setting using a new hand driven

tissue removal device, Resectr™ 5fr, is feasible in terms of installation and
resection time. To our knowledge, this is the first report on its clinical use.
6
Installation and resection times were short. The reported installation times
associated with mechanical hysteroscopic tissue removal systems (median
5.2 minutes) and resectoscopic surgery (median 4.5 minutes) were longer.
(18) This is explained by the simplified setup of the hand driven tissue
removal device. Our resection times were incomparable with those
reported in literature using 5fr. mechanical instruments, 5fr. bipolar
instruments, mechanical hysteroscopic tissue removal systems and
resectoscopic surgery in an office setting, because of heterogeneity in time
definitions, polyp sizes and polyp numbers.(13,14,16,17,19–24)
Our procedures were done by four experienced surgeons, with two surgeons
performing more interventions. Still, there was no indication that resection
times were different amongst the surgeons. It is already known that
mechanical hysteroscopic tissue removal systems have a shorter learning
curve compared to bipolar electrosurgery.(17,25)
The surgeons practical, comfort, and safety scores were high. These scores
were not yet reported on before in an office setting. Van Dongen et al
reported surgeon and trainer convenience scores on a visual analogue scale
(VAS), which was in favor of the mechanical hysteroscopic tissue remov-
al system compared to resectoscopic surgery.(25) Tsuchiya et al reported
CHAPTER 6 | 91
surgeon convenience with a mechanical hysteroscopic tissue removal system
and resectoscopic surgery in terms of maneuverability of the device, easi-
ness of removal and visibility on a VAS scale (26). VAS scores were 7.7, 8.4
and 7.8 for the mechanical hysteroscopic tissue removal system and 7.2, 6.5
and 6.4 for resectoscopic surgery, respectively. Stoll et al reported surgeon’s
comfort scores on a VAS scale of 8.4 and 7.4 for the mechanical hysteroscop-
ic tissue removal system and resectoscopic surgery, respectively.(27)
Patients reported low pain scores and high satisfaction scores. The reported
pain scores using 5r. mechanical instruments, 5fr. bipolar instruments,
mechanical hysteroscopic tissue removal systems and resectoscopic surgery
in an office setting are heterogeneous in terms of measure point (during or
after the procedure), measure scale (10 or 100 VAS scale) and analgesia use.
(16,17,20–24,28–30) The highest median score on a 10-point VAS scale was
3.6 using 5fr. mechanical instruments.(21) The highest median score on a
100-point VAS scale was 52.0 using 5fr bipolar instruments.(16) A Cochrane
meta-analysis showed no good-quality evidence of a clinically meaningful
difference in safety or effectiveness between different types of pain relief
compared with each other, with placebo, or with no treatment in women
undergoing a diagnostic hysteroscopy.(31) A more recent meta-analysis of
pain relief during diagnostic and operative hysteroscopy recommended
NSAIDs to reduce pain during and after the procedure.(32) However, a major
limitation of this meta-analysis is the methodologic and clinical
heterogeneity. Conflicting results exist whether mechanical
polypectomy is associated with lower VAS scores than electrosurgical
resection.(16,17,20,33) The reported satisfaction rates for hysteroscopic
polypectomy in an office setting were 92.5 on a 100-point VAS scale and
97.5% indicated that they were ‘very satisfied’ using a mechanical
hysteroscopic tissue removal system.(22,24)
There were particularities in three cases. It is remarkable that in all cases

the polyp was located posteriorly, whereas it is known that fundal polyps
may be hard to reach. A difficult resection of hard tissue may suggest that
the device is not suitable for myomectomy. Device deficiency may reflect
its fragility as well as the unsuitability to resect harder tissue. Conversion
rates regarding hysteroscopic polypectomy in an office setting were not yet
reported before. The reported complete polyp resection rates using 5fr
mechanical and 5fr bipolar instruments and mechanical hysteroscopic tissue
removal systems ranged from 77% to 97.5%.(16,17,24,28) The odds ratio
(OR) for complete polyp resection was significantly higher using the
mechanical hysteroscopic tissue removal system compared to 5fr bipolar
instruments (OR 12.5 (1.5 – 100.6)).[16] Most studies on hysteroscopic
polypectomy in an office setting, using 5fr mechanical and 5fr bipolar
instruments, mechanical hysteroscopic tissue removal systems or
resectoscopic surgery were without complications.(19,20,23,24,34)
Reported complications are vasovagal response, vomiting, pain and cervical
tears.(14,16,22,28)
92 | CHAPTER 6
There was no tissue available to send for pathology analysis in one case.
This was one of the first procedures. The ENDOMAT® SELECT tubing set is
long and it should be flushed to remove the tissue, especially if it contains a
small amount of tissue. This was therefore performed in all consecutive
procedures. Tissue availability related to other hysteroscopic techniques
were not yet reported before.
Our study has some limitations. Firstly, pain medication was not stan-
dardized and not blinded. This could have influenced our results (low pain
scores, high satisfaction rates). Nevertheless, this corresponds with the
reality in clinical practice. No procedure had to be discontinued because of
pain. The pain medication that was taken is non-invasive and safe. Secondly,
surgeon reported outcomes may be subjective, but it was multicentric and
different surgeons were involved. Thirdly, we did not take the cost into
account. Fourthly, only smaller polyps were included. However, this size was
chosen because it corresponds with the diameter of the internal cervical
ostium which is within the feasible range of 5fr mechanical instruments.
Lastly, we did not have a control group. Whether a randomized controlled
trial (RCT) is worth the effort is, in accordance with the IDEAL framework,
evaluated through this feasibility study.
Future research focusing on hysteroscopic polypectomy in an office setting

should be conducted. The Resectr™ 5fr and 5fr. mechanical instruments
should be compared in terms of clinical and cost effectiveness.
The maximum polyp size suitable for resection with the Resectr™ 5fr should
be determined and subsequently a comparison with 5fr bipolar instruments
should be done. In addition, other indications should be examined (targeted
biopsy and retained products of conception).
6
In conclusion, hysteroscopic removal of polyps with mean diameter ≤ 8mm,
using the Resectr™ 5fr in an office setting, is feasible in terms of installation
time and resection time. The surgeon’s practical, comfort, and safety scores
are high, whereas women report low pain scores and high satisfaction rates.
Future research should be conducted focusing on the comparison with other
techniques and other indications.
CHAPTER 6 | 93
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CHAPTER 6 | 95
PART III
REPRODUCTIVE OUTCOME AFTER OPERATIVE HYSTEROSCOPY
CHAPTER 7
Reproductive and obstetric outcomes
after hysteroscopic removal of
retained products of conception
Steffi van Wessel

Nele Coryn
Hubertus van Vliet
Benedictus Schoot
Steven Weyers
Tjalina Hamerlynck
J Minim Invasive Gynecol. 2020;27(4):840-6

ABSTRACT
Study Objective To evaluate the reproductive outcomes in women treated

for retained products of conception (RPOC) by hysteroscopy (morcellation vs
loop resection).
Design Cohort study.
Setting A teaching and university hospital.
Patients Patients included in a previous randomized controlled trial on

hysteroscopic removal of RPOC comparing morcellation (n = 46) with loop
resection (n = 40).
Interventions Hysteroscopic morcellation versus loop resection.
Measurements and Main Results The primary outcome measures were live
birth and pregnancy complications (including abnormal placentation
[placenta accreta/increta/percreta], placenta previa, vasa previa, retained
placenta after delivery or incomplete expulsion with the need for manual
removal or curettage, and RPOC), uterine rupture, and other complications
(blood loss, preterm labor, preterm premature rupture of membranes,
hypertensive disorders of pregnancy, and intrauterine growth restriction).
The live birth rate was 88.9% in the morcellation group and 68.2% in the
loop resection group (p = .09). Uterine rupture occurred in 1 patient in the
morcellation group (4.2%) (p = 1.00). Placental complications were found in
20.8% and 22.2% of the hysteroscopic morcellation and loop resection
groups, respectively (p = .33), and other pregnancy complications were seen
in 33.3% and 16.6% of the 2 groups (p = .33). The secondary outcome was
time to pregnancy. The median time to pregnancy was 14 weeks
(interquartile range [IQR], 5−33 weeks) in the morcellation group and 15
weeks (IQR, 6−37 weeks) in the loop resection group (p = .96).
Conclusion Hysteroscopic removal of RPOC seems to have no detrimental

effect on reproductive outcome and no significant effect on pregnancy rate.
100 | CHAPTER 7
INTRODUCTION
Retained products of conception (RPOC) consist of intrauterine tissue that

develops after conception and persists after miscarriage, termination of
pregnancy, vaginal delivery, or cesarean section delivery (1).
Hysteroscopy is a more recent approach to remove RPOC compared with
dilation and curettage (D&C). In loop resection, RPOC are removed using a
resectoscope, preferably without electric current (cold loop). Cohort studies
show that compared with D&C, loop resection is associated with a lower
incidence of intrauterine adhesions and more complete evacuation
(p < .001) (2). According to the review published by Hooker et al (2), loop
resection and D&C seem to have no statistically significant differences in
conception rate (overall 82%) and ongoing pregnancy/live birth rate (overall
73%). However, the mean time to conception is significantly shorter after
removal of RPOC by loop resection in various reports: 7.3 months vs 11
months (p < .03) reported by Cohen et al (3), 27 months vs 34 months
(p = .036) reported by Rein at al (4), and 7.4 months vs 12.9 months
(p = .05) reported by Ben Ami et al (5).
Morcellation is a newer hysteroscopic technique for RPOC removal. In our

randomized controlled trial (RCT) comparing morcellation and loop
resection, morcellation was significantly faster (median operating time, 10.0
minutes [interquartile range (IQR), 5.8 − 16.4 minutes] vs 6.2 minutes [IQR,
4−11.2 minutes]; p = .023) (6). Both techniques were safe procedures and
had a low rate of de novo adhesions (3% for both techniques).
The reproductive and obstetric outcome after RPOC removal by
morcellation has not yet been reported.
Here we report a follow-up study evaluating the reproductive and obstetric

outcomes of patients treated for RPOC by hysteroscopy, comparing
morcellation and loop resection.
7
This retrospective follow-up study was conducted in 2018 and was approved
by the Ethics Committee of Ghent University Hospital (Belgium) and
Catharina Hospital (Eindhoven, The Netherlands). The study has been
registered at ClinicalTrials.gov (identifier NCT01537822).
The study population comprised the participants of a previous RCT

comparing 2 hysteroscopic techniques for the removal of RPOC: loop
resection (n = 40) and morcellation (n = 46). The study was conducted
between May 2011 and July 2015 in 2 centers: a university hospital (Ghent
University Hospital; n = 35) and a teaching hospital (Catharina Hospital;
n = 51) (6). Detailed descriptions of the hysteroscopic techniques used in
the RCT are provided in the original report. The aim of the original RCT was
CHAPTER 7 | 101
to compare hysteroscopic morcellation and loop resection for the removal
of placental remnants in terms of procedure time, adverse events, tissue
availability, histology results, short-term effectiveness, and postoperative
adhesions. The median operating time was significantly shorter for
hysteroscopic morcellation compared with loop resection (6.2 minutes
[interquartile range (IQR), 4.0−11.2 minutes] vs 10.0 minutes [IQR, 5.8−16.4
minutes]; p = .023). No adverse events occurred during hysteroscopic
removal. Perforation at dilation in 8 cases of the hysteroscopic morcellation
group resulted in 2 procedure discontinuations and 1 incomplete procedure.
Incomplete removal was found in 1 uncomplicated hysteroscopic
morcellation procedure and 2 resection procedures.Pathology results
confirmed the presence of placental remnants in 27 of 40 patients (67.5%)
in the hysteroscopic morcellation group and in 26 of 37 patients in the loop
resection group. Second-look hysteroscopy showed de novo intrauterine
adhesions in 1 of 35 patients (3%) in the hysteroscopic morcellation group
and in 1 of 30 patients (3%) in the loop resection group.
In the present follow-up study, we aimed to study the reproductive and

obstetric outcome of patients treated for RPOC by hysteroscopy,
comparing morcellation with loop resection. All patients included in the
follow-up study gave informed consent. All cases were reviewed for
reproductive and obstetric outcomes of the first pregnancy subsequent to
the treatment of RPOC.
The primary outcome measures were live birth and pregnancy

complications. Live birth was defined as the complete expulsion or
extraction from the mother of a product of fertilization, irrespective of the
duration of pregnancy, which after such separation breathes or shows any
other evidence of life, such as heartbeat, umbilical cord pulsation, or
definite movement of voluntary muscles, irrespective of whether the
umbilical cord has been cut or the placenta is attached (7).
Pregnancy complications were subdivided into placental complications
(including abnormal placentation [placenta accreta, increta, percreta,
previa, or vasa previa], retained placenta after delivery/expulsion with the
need for manual removal or curettage, and RPOC), uterine rupture and
other pregnancy complications (blood loss in the first, second, and/or third
trimester [≤12 weeks, 12 to ≤28 weeks, and >28 weeks of gestational age,
respectively), preterm labor, preterm premature rupture of membranes,
hypertensive disorder of pregnancy (including pregnancy-induced
hypertension and preeclampsia and/or eclampsia), and intrauterine growth
restriction (IUGR; small for gestational age, defined as birth weight <2 SD
below the mean or <10th percentile according to local intrauterine growth
charts).
The secondary outcome variable was time to pregnancy, measured in weeks

from the start of attempts to conceive until conception. Clinical pregnancy
was defined as a pregnancy diagnosed by ultrasonographic visualization of 1
or more gestational sacs or definitive clinical signs of pregnancy (7); ectopic
102 | CHAPTER 7
pregnancy was included. Multiple gestational sacs were counted as 1
clinical pregnancy. Miscarriage was defined as the spontaneous loss of a
clinical pregnancy before 20 completed weeks of gestational age (18 weeks
after fertilization) or, if gestational age was unknown, the loss of an
embryo/fetus weighing <400 g (7).
Other pregnancy outcomes, including birth weight, start of delivery

(spontaneous, induction, or primary caesarean section), delivery mode
(spontaneous, vaginal assisted delivery by vacuum or forceps extraction, or
secondary section), and gestational age at delivery, were reported for the
live births. In cases of postpartum hemorrhage, defined as blood loss of ≥500
mL within 24 hours after delivery, the need for treatment by uterotonics,
manual removal of the placenta, curettage, embolization, Bakri balloon
placement, or hysterectomy was noted. The need for blood transfusion after
delivery was also recorded.
Data were collected and analyzed with SPSS version 25 (IBM, Armonk, NY).
For symmetrically distributed continuous variables, means, SDs, and 95%
confidence intervals (CIs) were reported, and the mean differences were
analyzed using the Student t test. For nonsymmetrically distributed
continuous variables, median, IQR, minimum and maximum were computed
and analyses was performed using the Mann−Whitney U test. Categorical
data were presented as frequency and percentage and analyzed using the
x2 test or Fisher’s exact test. Firth logistic regression was used to analyze
the primary outcome measures if the univariate analysis was significantly
different. Time to pregnancy was analyzed using a time-to-event analysis.
A p value <.05 was considered to indicate statistical significance. Both an
intention-to-treat analysis and a per-protocol analysis were performed.
RESULTS
The total response rate was 80.2% (69 of 86 patients). The patients’ 7
responses are summarized in Figure 1. Three out of 86 women (3.5%)
refused participation, and 14 (16.3%) were lost to follow-up, leaving 69
women in the study cohort.
After hysteroscopic removal of RPOC, 49 of the 69 women (71%) wished to

reconceive, including 27 of 39 (69.2%) in the morcellation group and 22 of
30 (73.3%) in the loop resection group (p = .71). Demographic characteristics
of the intention-to-treat groups are presented in Table 1. There were no
statistically significant betweengroup differences. The median follow-up
was 4 years (IQR, 4−6 years) in the morcellation group and 5 years (IQR, 4−5
years) in the loop resection group (p = .90).
Descriptive data on reproductive outcomes are presented in Table 2.

Conception via assisted reproduction was attempted by 4 of 27 women
CHAPTER 7 | 103
(14.8%) in the morcellation group and in 2 of 20 women (10%) in the loop
resection group (p = 1.00). In the morcellation group, ovulation induction
was performed in 1 of the 4 women (25%), intrauterine insemination in a
stimulated cycle in 2 of 4 (50%), and in vitro fertilization/ intracytoplasmic
sperm injection in 1 of 4 (25%). In the resection group, ovulation induction
and intrauterine insemination in a stimulated cycle were each performed in
1 patient (50% for each). Conception occurred in 24 women in the
morcellation group (88.9%) and in 19 women in the loop resection group
(86.4%).
Figure 1 Patient responses
hysteroscopic
loop resection morcellation
n=40 n=46
lost to follow-up lost to follow-up

n=9 n=5
refused to refused to
participate participate
n=1 n=2
included for included for

follow-up follow-up
n=30 n=39
desired new desired new

pregnancy pregnancy
n=22 n=27
Table 1 Demographic characteristics
104 | CHAPTER 7
Table 2 Reproductive outcome
The primary outcome measure, live birth, occurred in 24 of 27 women

(88.9%) in the morcellation group and in 15 of 22 (68.2%) in the loop
resection group; the difference was not statistically significant (p = .09).
The other primary outcome measure (pregnancy complications, subdivided

into placental complications, uterine rupture, and others) is summarized in
Table 3. There were no significant between-group differences in this
measure.
Table 3 Pregnancy outcome
CHAPTER 7 | 105
Abnormal placentation occurred as placenta accreta in 1 of 24 women
(4.2%) in the morcellation group and as 1 case each of placenta accreta and
placenta previa (2 of 14; 14.3%) in the loop resection group (p = .54). In the
morcellation group, RPOC occurred after manual removal of the placenta
subsequent to vaginal delivery/expulsion in 1 of 24 women (4.2%). In the
loop resection group, RPOC occurred in 2 of 17 women (11.8%) after
placenta accreta and after pregnancy termination because of
cytomegalovirus infection (p = .63).
Uterine rupture occurred in 1 of 24 women (4.2%) in the morcellation group

(p = 1.0), a patient with a hemi-uterus (European Society of Human
Reproduction and Embryology/European Society for Gynaecological
Endoscopy class U4b) in whom perforation had occurred during dilation of
the cervix preceding the hysteroscopic procedure (8). The remnants could
be removed using the tip of a 5-mm Bettocchi hysteroscope (Karl Storz,
Tuttlingen, Germany). During the subsequent pregnancy, the patient was
admitted at 36 weeks 5 days for sudden onset of severe abdominal pain.
Maternal hypotension (81/53 mm Hg) and fetal distress were noted, and an
ultrasound examination revealed intraabdominal fluid. An urgent caesarean
section was performed,leading to a diagnosis of hemoperitoneum caused by
uterine rupture on the posterior side of the uterus (site of the perforation).
A male infant was born with birth weight 2388 g, Apgar 1-4-9. Magnetic
resonance imaging of the neonate for peripartal asphyxia was negative.
In the morcellation group, all 3 pregnancies (3 of 24; 12.5%) with first

trimester blood loss resulted in live births, whereas in the loop resection
group, the sole pregnancy complicated by first trimester blood loss
resulted in a miscarriage (1 of 18; 5.5%; p = .62). The 2 cases of blood loss in
the third trimester in the morcellation group were not related to placental
complications and resulted in 2 live births, and the 1 case of third trimester
blood loss in the loop resection group was related to placenta previa and
also ended in a live birth. In the morcellation group, 1 of 24 pregnancies
(4.2%) was complicated by preterm labor near term, which nevertheless led
to a term delivery (p = 1.0). IUGR occurred in 3 of 24 pregnancies (12.5%) in
the morcellation group and was not related to pregnancy-induced
hypertension (p = .28).
The secondary outcome measure, time to pregnancy, was 14 weeks (IQR,

5−33 weeks) in the morcellation group and 15 weeks (IQR, 6−37 weeks) in
the loop resection group (p = .96). Additional data on the live births are
presented in Table 4. No significant between-group differences were seen.
The results of the per-protocol analysis were comparable to those of the

intention-to-treat analysis. There were no statistically significant
differences in the primary and secondary outcomes. The 1 case of uterine
rupture was not withheld in the per-protocol analysis, because this patient
was not treated by the allocated technique (hysteroscopic morcellation)
owing to uterine perforation at the time of dilation.
106 | CHAPTER 7
Table 4 Descriptive data for live birth
CHAPTER 7 | 107
7
DISCUSSION
To our knowledge, this is the first report comparing the reproductive and
obstetric outcomes between hysteroscopic morcellation and loop resection
for the removal of RPOC. Moreover, no previous data were available on
reproductive and obstetric outcomes after hysteroscopic morcellation.
The pregnancy rates in the present study were higher than those reported
in other studies (15%−82%) (9−14). The live birth rate of 68.2% in the loop
resection group was comparable to the rates reported for loop resection in
other studies (69%−75%) (9−13). The live birth rate was higher in the
morcellation group (88.9%), although the difference was not statistically
significant. We acknowledge our small sample size in the context of live
births.
There were no significant between-group differences in overall placental

complications. More specifically, no significant differences between the 2
study groups were observed in the rates of abnormal placentation, retained
placenta after delivery with the need for manual placental removal, or
persistence of RPOC. Furthermore, the occurrence of placental
complications was not significantly influenced by previous cesarean section
(p = .40). Comparison with other studies is not straightforward, given the
different definitions of placental complications. The study of Ikhena et al
(11) describing reproductive outcomes after hysteroscopic resection of RPOC
showed an 18% rate of abnormal placentation, defined as placenta accreta,
increta and percreta, vasa or placenta previa, and retained placenta.
Ben Ami et al (5) reported placental complications in 11% of their patients
who underwent hysteroscopic removal of RPOC; however, they did not
describe the subtypes of abnormal placentation analyzed. In our study,
4 patients in the morcellation group required manual removal of the
placenta after delivery, compared with 1 patient in the loop resection
group, a non−statistically significant difference. Hysteroscopic morcellation
and cold loop resection are mechanical techniques that involve only limited
damage to the surrounding healthy endometrium. Placental complications
may be related to retained products of conception rather than to the
surgical technique.
Before labor, near-term uterine rupture occurred in 1 woman with a hemi-

uterus at 3 years after the hysteroscopic procedure. According to the
Belgian Obstetric Surveillance System, the estimated prevalence of uterine
rupture in Belgium is 3.6 (95% CI, 2.9−4.4) per 10,000 deliveries, which is
comparable to the prevalence reported by the World Health Organization
(0.03% in developed countries). Known risk factors for uterine rupture
include scarring from a previous caesarean section, gestational age >37
weeks, labor, and induction or augmentation of labor (15). Evidence for the
risk of uterine rupture following complicated operative hysteroscopy
remains inconclusive, with only case reports included in the literature.
Five of the other 7 patients who sustained uterine perforation in the initial
108 | CHAPTER 7
RCT became pregnant; none experienced any adverse obstetric events.
Data on other complications of pregnancy after hysteroscopic RPOC are very

scarce. Ben Ami et al (5) and Ikhena et al (11) have reported rates of IUGR
and preterm birth in pregnancies following surgical removal of RPOC. Both
studies compared these outcomes between D&C and hysteroscopic resection
and found no significant differences.
The secondary outcome measure, time to pregnancy, also was not

statistically different between the loop resection and morcellation groups.
Other studies have demonstrated a significantly shorter mean time to
conception after RPOC removal by loop resection compared with D&C: 7.3
months vs 11 months (p < .03) reported by Cohen et al (3), 27 months vs 34
months (p = .036) reported by Rein at al (4), and 7.4 months vs 12.9 months
(p = .05) reported by Ben Ami et al (5). Sonnier et al (12) reported an
average time to conception of 22 weeks after RPOC removal by loop
resection. Our interval was markedly shorter.
Our present follow-up study is limited by its retrospective design, and

although the response rate was high, we could not obtain reproductive
outcome data for 17 of 86 patients (19.8%) included in the initial RCT. This
might have affect our outcome data. Furthermore, although we tried to
minimize missing data, some variables were lacking. Part of the
evaluation was done by telephone interview, which may be associated with
recall bias. Although our sample size was not small compared with other
studies, nonsignificant differences may be related to insufficient power. In
addition, roughly onethird of the patients did not ultimately have a
pathological diagnosis of retained products, limiting our ability to draw
conclusions.
In conclusion, this study provides information on how hysteroscopic

treatment of RPOC may affect future reproductive and obstetric outcomes.
Hysteroscopic removal of RPOC using loop resection or morcellation seems 7
to have no detrimental effect on reproductive outcomes, and rates of
subsequent pregnancy do not differ significantly between the 2 techniques.
Uterine rupture can occur after entry-related perforation in patients with a
congenital uterine anomaly. Our results show placental complications in
1 of 5 women after hysteroscopic removal of RPOC. The results from ongoing
RCTs will further guide clinicians toward choosing the best treatment (16).
Furthermore, health economic analyses comparing loop resection to the
more costly hysteroscopic morcellator for the removal of RPOC are needed.
CHAPTER 7 | 109
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outcome after the management of retained products of conception: a systematic review.
Fertil Steril. 2016;105:156–164. e2.
(3) Cohen SB, Kalter-Ferber A, Weisz BS, et al. Hysteroscopy may be the method of choice for
management of residual trophoblastic tissue. J Am Assoc Gynecol Laparosc. 2001;8:199–202.
(4) Rein DT, Schmidt T, Hess AP, Volkmer A, Schöndorf T, Breidenbach M. Hysteroscopic
management of residual trophoblastic tissue is superior to ultrasound-guided curettage.
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(5) Ben-Ami I, Melcer Y, Smorgick N, Schneider D, Pansky M, Halperin R. A comparison of

reproductive outcomes following hysteroscopic management versus dilatation and curettage of
retained products of conception. Int J Gynecol Obstet. 2014;127:86–89.
(6) Hamerlynck TW, van Vliet HA, Beerens AS, Weyers S, Schoot BC. Hysteroscopic morcellation
versus loop resection for removal of placental remnants: a randomized trial. J Minim Invasive
Gynecol. 2016;23:1172–1180.
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Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization
(WHO) revised glossary of ART terminology, 2009. Fertil Steril. 2009;92:1520–1524.
(8) Grimbizis GF, Di Spiezo Sardo A, Saravelos SH, et al. The Thessaloniki ESHRE/ESGE consensus
on diagnosis of female genital anomalies. Hum Reprod. 2016;31:2–7.
(9) Golan A, Dishi M, Shalev A, Keidar R, Ginath S, Sagiv R. Operative hysteroscopy to remove
retained products of conception: novel treatment of an old problem. J Minim Invasive Gynecol.
2011;18:100–103.
(10) Faivre E, Deffieux X, Mrazguia C, et al. Hysteroscopic management of residual

trophoblastic tissue and reproductive outcome: a pilot study. J Minim Invasive Gynecol.
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(11) Ikhena DE, Bortoletto P, Lawson AK, et al. Reproductive outcomes after hysteroscopic
resection of retained products of conception. J Minim Invasive Gynecol. 2016;23:1070–1074.
(12) Sonnier L, Torre A, Broux P, Fauconnier A, Huchon C. Evaluation of fertility after operative
hysteroscopy to remove retained products of conception. Eur J Obstet Gynecol Reprod Biol.
2017;211:98–102.
(13) Jiménez JS, Gonzalez C, Alvarez C, Muñoz L, Pérez C, Muñoz JL. Conservative management
of retained trophoblastic tissue and placental polyp with diagnostic ambulatory hysteroscopy.
Eur J Obstet Gynecol Reprod Biol. 2009;145:89–92.
(14) Fuchs N, Smorgick N, Ben Ami I, et al. Intercoat (Oxiplex/AP gel) for preventing intra-
uterine adhesions after operative hysteroscopy for suspected retained products of conception:
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(15) Vandenberghe G, De Blaere M, Van Leeuw V, et al. Nationwide population-based cohort

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BMJ Open. 2016;6:e010415.
(16) Hamerlynck TWO, Meyers D, Van der Veken H, Bosteels J, Weyers S. Fertility outcome after
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treatment of retained products of conception. Gynecol Surg. 2018;15:12
CHAPTER 7 | 111
CHAPTER 8
Anti-adhesion Gel versus No gel following
Operative Hysteroscopy prior to Subsequent
fertility Treatment or timed InterCourse
(AGNOHSTIC), a randomised controlled trial:
protocol
Steffi van Wessel

Tjalina Hamerlynck
Valerie Schutyser
Carla Tomassetti
Christine Wyns
Michelle Nisolle
Jasper Verguts
Roos Colman
Steven Weyers
Jan Bosteels
Hum Reprod Open. 2021;2021(1):hoab001

ABSTRACT
Study questions Does the application of anti-adhesion gel, compared to

no gel, following operative hysteroscopy to treat intrauterine pathology in
women wishing to conceive increase the chance of conception leading to
live birth?
What is known already Intrauterine adhesions (IUAs) following operative

hysteroscopy may impair reproductive success in women of reproductive
age. Anti-adhesion barrier gels may decrease the occurrence of IUAs, but
the evidence on their effectiveness to improve reproductive outcomes is
sparse and of low quality.
Study design, size, duration This multicentre, parallel group, superiority,

blinded and pragmatic randomised controlled trial is being carried out in
seven participating centres in Belgium. Recruitment started in April 2019.
Women will be randomly allocated to treatment with anti-adhesion gel
(intervention group) or no gel (control group). Sterile ultrasound gel will be
applied into the vagina as a mock-procedure in both treatment arms. The
patient, fertility physician and gynaecologist performing the second-look
hysteroscopy are unaware of the allocated treatment. Power analysis, based
on a target improvement of 15% in conception leading to live birth using
anti-adhesion gel, a power of 85%, a significance level of 5%, and a drop-out
rate of 10%, yielded a number of 444 patients to be randomised.
The baseline rate of conception leading to live birth in the control group is
expected to be 45%.
Participants/materials, setting, methods Women of reproductive age

(18–47 years), wishing to conceive (spontaneously or by fertility treatment)
and scheduled for operative hysteroscopy to treat intrauterine pathology
(endometrial polyps, myomas with uterine cavity deformation, uterine
septa, IUAs or retained products of conception) are eligible for recruitment.
Women may try to conceive from 3 to 6 weeks after receiving allocated
treatment with follow-up ending at 30 weeks after treatment. If the woman
fails to conceive within this timeframe, a second-look hysteroscopy will be
scheduled within 2–6 weeks to check for IUAs. The primary endpoint is
conception leading to live birth, measured at 30 weeks after randomisation.
The secondary endpoints are time to conception, clinical pregnancy,
miscarriage and ectopic pregnancy rates, measured at 30 weeks after
receiving allocated treatment. The long-term follow-up starts when the
patient is pregnant and she will be contacted every trimester.
114 | CHAPTER 8
INTRODUCTION
Several intrauterine anomalies, including endometrial polyps, myomas with

uterine cavity deformation, uterine septa, intrauterine adhesions (IUAs)
and retained products of conception (RPOC), have been linked with female
fertility problems (1–4). Hysteroscopy is considered to be the gold standard
to treat these intrauterine pathologies. The evidence in favour of operative
hysteroscopy for improving reproductive success in women with
endometrial polyps, myomas with uterine cavity deformation, uterine septa,
IUAs or RPOC is sparse and of moderate to low quality. Nevertheless,
hysteroscopy is very often performed, especially in women attending
fertility clinics because among the medical community the presence of
intrauterine pathology distorting the uterine is widely believed to impair
reproductive outcome. A major long-term complication of operative
hysteroscopy is the formation of IUAs (5–7). The reported incidence of
postsurgical IUAs at second-look hysteroscopy is 3.6% after polypectomy,
6.7% after resection of uterine septa, 31% after removal of a solitary
myoma, 45% after resection of multiple myomas and 3% after removal of
RPOC.
IUAs are fibrous strings at opposing walls of the uterus, developing after
injury to the basal layer of the endometrium (8,9). Reviews of large
observational studies have demonstrated an association between IUAs and
poor reproductive outcome, namely a prevalence of infertility as high as 43%
and recurrent pregnancy loss in 22% (9–11). Moreover, there is an increased
risk of obstetrical complications after successful hysteroscopic adhesiolysis,
for example abnormal placentation, preterm delivery, uterine rupture and
peripartum hysterectomy (12).
Women of reproductive age wishing to conceive may benefit from the IUA
prevention following operative hysteroscopy. However, the optimal anti-
adhesion strategy still needs to be defined because data from high quality
studies on the effectiveness of anti-adhesion treatment for improving
reproductive outcomes are sparse and of low quality. A Cochrane meta-
analysis of five randomised controlled trials (RCTs) has demonstrated that
the use of anti-adhesion gel may decrease the occurrence of IUAs at
second-look hysteroscopy compared to no treatment or placebo (odds ratio
(OR) 0.37, 95% confidence interval (CI) [0.21 - 0.64]; P < .01). The overall
quality of the body of evidence retrieved was low and data on live birth
8
rates were lacking (13–18).
In summary, uncertainty remains on the effectiveness of the use of anti-

adhesion barrier gels following operative hysteroscopy for women wishing
to conceive. In order to address this knowledge gap, our group has designed
the AGNOHSTIC trial (Anti-adhesion Gel versus No gel following Operative
Hysteroscopy prior to Subsequent fertility Treatment or timed InterCourse).
CHAPTER 8 | 115
OUTCOMES
The primary endpoint of the study is conception leading to live birth,

measured at 30 weeks after randomisation.
Secondary endpoints are time to conception, rates of clinical pregnancy,

miscarriage and ectopic pregnancy 30 weeks after receiving allocated
treatment, IUA rate and course of pregnancy.
For the definition of the reproductive outcomes we have followed the

guidance of The International Committee for Monitoring Assisted
Reproductive Technology (ICMART) (19).
Live birth is defined as the delivery of at least one live foetus after 20
completed weeks of gestation, that resulted in at least one live baby.
We will count the delivery of singleton, twin or multiple pregnancies as one
live birth.
Time to pregnancy is defined as the time from receiving allocated treatment

to the date of conception retrospectively determined based on the crown-
rump length measurement (CRL) by a first-trimester ultrasound (US).
Clinical pregnancy is defined as an US visible gestational sac. It includes

ectopic pregnancy. We count multiple gestational sacs as one clinical
pregnancy.
Miscarriage is defined as spontaneous loss of pregnancy before 20 completed

weeks of gestation, or if gestational age is unknown, a birth weight of less
than 400 gram.
Ectopic pregnancy is defined as a pregnancy in which implantation takes

place outside the uterine cavity.
IUAs are measured at second-look hysteroscopy in women that failed to

conceive during the follow-up period. The severity of the adhesions is scored
according to the American Fertility Society (AFS) classification (20).
The course of pregnancy is registered in all women who conceive during

the follow-up period, leading to a pregnancy beyond 20 weeks of gestation.
Items of interest include pre-eclampsia, preterm birth, stillbirth, low/very
low birth weight, caesarean section rate and neonatal complications
(respiratory distress syndrome, intrapartum asphyxia, neonatal seizures,
admission to the neonatal intensive care unit, congenital malformations).
Table 1 provides an overview of the outcome measures.
116 | CHAPTER 8
Table 1
Overview of outcome measures in a randomised controlled trial of anti-adhesion gel versus no gel following
operative hysteroscopy in women who wish to conceive.
Study design
The AGNOHSTIC trial is a multicentre, pragmatic, parallel group, superiority,
blinded RCT.
Ethical review and trial registration

The study was approved by the central (Ghent University Hospital (670),
EC/2019/0100) and local Ethical Committees of the participating centres.
Written informed consent of the participants will be obtained before
randomisation. The study protocol has been registered at Clinicaltrials.gov
(NCT03880435, March 19, 2019).
Patient population
We will include women of reproductive age (18 to 47 years), wishing to
conceive (spontaneously or by fertility treatment) and scheduled for
operative hysteroscopy to treat intrauterine pathology (endometrial polyps,
myomas with uterine cavity deformation, uterine septa, IUAs or RPOC).
A CONSORT flow chart will be provided.
The mode of conception is in accordance with standard clinical practice in

Belgium. Because of the pragmatic character of the trial, women will be
allowed to switch from category A (spontaneous conception) to category B
(fertility treatment) or switch to a different treatment within category B
based on medical indications.
8
Intrauterine pathology will be detected by US, saline-infusion-sonography
(SIS), magnetic resonance imaging (MRI) or hysterosalpingography (HSG) and
confirmed by diagnostic hysteroscopy according to standard clinical
practice in Belgium. If in exceptional circumstances the diagnostic
hysteroscopy cannot be done and/or it is very likely that pathology is
present based on other imaging techniques (for example MRI), the woman
will be considered eligible and operative hysteroscopy will be scheduled.
Endometrial polyps are focal endometrial outgrowths containing glands,
CHAPTER 8 | 117
stroma and blood vessels (21). They appear as hyperechogenic structures
on US with regular contours, occupying the uterine cavity, surrounded by a
small hypoechogenic halo. Colour Doppler can be used to detect the
vascular stalk.
Myomas derive from myometrial cells and they may protrude into the
uterine cavity (22). They are classified according to their anatomical
location (PALM-COEIN classification) and in this study myomas with cavity
deformation, suitable for resection by hysteroscopy, will be included (23).
These are submucosal myomas type 0, 1 and 2 (entirely within the uterine
cavity, < 50% and ≥ 50% myometrial extension, respectively), and intramural
myomas sufficiently large to distort the uterine cavity (hybrid myomas type
2-5) suitable for complete resection by hysteroscopy. The extent of cavity
protrusion is clinically relevant for predicting the successful outcome of
hysteroscopic myomectomy (24).
A uterine septum is a congenital uterine malformation. According to the

European Society of Human Reproduction and Embryology (ESHRE) /
European Society for Gynaecological Endoscopy (ESGE) classification system
for female genital tract congenital anomalies, it is defined as a uterus with
a normal outline and an internal indentation at the fundal midline
exceeding 50% of the uterine wall thickness (Class U2) (25).
IUAs, scar tissue that sticks the uterine walls together, are classified
according to the AFS classification (20).
RPOC consist of intrauterine tissue that develops after conception and

persists after miscarriage, termination of pregnancy, vaginal delivery or
caesarean section (26).
The presence of extrauterine pathology that may affect women’s fertility is

allowed.
Women will be excluded if they are younger than 18 years or 48 years or

older, if they have a known allergy to auto-crosslinked polysaccharide (ACP)
gel or vaginal ultrasound gel, if they have an active infection of the genital
tract proven by genital swabs for polymerase chain reaction (PCR)
(Chlamydia, gonorrhoea) or endometrial biopsy (endometritis) both
performed if suspected based on clinical symptoms (abdominal pain, vaginal
discharge or bleeding problems), if other myomas (PALM-COEIN classification
type 3 and 4 intramural (entirely in the myometrium with or without
endometrial contact, respectively), types 5 to 7 subserosal (protruding
towards the abdominal cavity with <, ≥ 50% myometrial extension or
pedunculated, respectively) and type 8 other (cervical, parasitic)) are
present as the sole uterine pathology, if different types of intrauterine
pathology are present preoperatively, if they have no pregnancy wish and if
they already have participated in the trial.
118 | CHAPTER 8
Recruitment procedure
Women attending Belgian hospitals, fulfilling the inclusion criteria will be
invited to take part in the study. Initially, recruitment was started in 6
centres (Ghent University Hospital, University Hospital Brussels, University
Hospital Leuven, Cliniques Universitaires Saint-Luc Brussels, Centre
Hospitalier Universitaire Liège and Imelda Hospital Bonheiden). To speed up
the recruitment, an additional centre (Jessa Hospital Hasselt) has joined the
group in 2020.
Recruitment has started since April 2019 and is ongoing. The planned study
period will be 4.5 years.
Randomisation
All eligible women who provided written informed consent will be
randomised from one day up to 1 hour before the operative hysteroscopy.
The study is a parallel-group RCT with a 1:1 allocation ratio and stratified
randomisation with computer generated random permuted blocks of
variable sizes to avoid that the surgeon may predict the treatment
allocation.
The stratification factors are centre (seven categories) and type of

pathology treated by hysteroscopy (five categories).
Study drug
The intervention under study is the application of an anti-adhesion gel,
namely Hyalobarrier® gel endo (Nordic Pharma), after the complete
removal of intrauterine pathology (endometrial polyps, myomas with uterine
cavity deformation, uterine septa, IUAs or RPOC) by hysteroscopy. A second
operation will be planned in case of incomplete pathology removal. The
anti-adhesion gel is sterile, transparent and highly viscous, made from ACP
obtained by condensation of hyaluronic acid. Due to its viscosity, it keeps
the surrounding tissue separate during the recovery period after surgery.
Seven days after application in the uterine cavity, the gel is fully absorbed
(27). In the uterine cavity it is shown to remain in situ for at least 72 hours
(13). Yang et al showed a different endometrial healing process for various
hysteroscopic procedures (28). The shortest time period occurred after
polypectomy (1-2 months), and the longest time period was seen after
myomectomy. Whether the time frame of 72 hours is sufficient remains
to be seen. The effectiveness of Hyalobarrier® gel has been demonstrated 8
during surgical procedures in the abdomen and pelvis during clinical studies
(13,17,29-35). It is indicated for use in laparoscopic and hysteroscopic
procedures and is available as single-use disposable syringe. Each syringe
contains 10 ml of sterile gel containing 30 mg of ACP per ml.
For administration, individually packaged cannulas of 30 cm length are
enclosed. All reportable adverse events will be recorded in the patient’s
file and in the electronic Case Report Form (e-CRF) between randomisation
and the last trial related activity. Medical events that occur between signing
of the Informed Consent and the randomisation will be documented on the
CHAPTER 8 | 119
medical and surgical history section and concomitant diseases page of the
e-CRF. Additionally, all Serious Adverse Device Effects (SADE),
Unanticipated Serious Adverse Device Effects (USADE), incidents and other
significant safety issues will be reported immediately but no later than 3
calendar days after investigational site study personnel’s awareness of the
event to the sponsor and chief investigator. A detailed listing of our safety
reporting is shown in supplement 1. No gel will be applied in the uterine
cavity of women assigned to the control group.
The patient, fertility physician and gynaecologist performing the

second-look hysteroscopy will be unaware of the allocated treatment.
To ensure blinding, and to rule out a treatment effect of placebo gel applied
in the uterine cavity, sterile ultrasound gel will be applied into the vagina
in both treatment arms. The surgeons doing the operative hysteroscopy
cannot be blinded. If the fertility physician or the gynaecologist doing the
second-look hysteroscopy has also done the operative hysteroscopy, blinding
will be assured by notification of treatment allocation to another caretaker
(colleague gynaecologist or resident) after the surgeon has left the
operating room. The gel will subsequently be applied by this caretaker.
The biostatistician and the study nurses were blinded and did not take any
decision with respect to the further treatment and/or follow-up of the study
participants.
Co-treatment with hormonal medication may be given or repeated SIS or

hysteroscopy may be scheduled for severe IUAs, according to the standard
practice of the participating centre. This decision should be made before
the notification of the treatment allocation.
Follow up
The trial flow chart is shown in Figure 1. According to local practice, 3 to 6
weeks after the operative hysteroscopy with complete pathology removal,
women will be scheduled for a postoperative visit (telephone or physical) or
a second-look hysteroscopy. Subsequently, they may start trying to conceive
by regular sexual intercourse or fertility treatment (4-6 cycles ovulation
induction (OI), 4-6 cycles controlled ovarian stimulation (COS) or 4-6 cycles
intrauterine insemination (IUI) or 3 embryo transfers). Women will be
contacted every month to check if they are pregnant.
The short-term follow-up ends 30 weeks after randomisation for the primary
endpoint. This is in concordance with the CONSORT guidelines (36).
Secondary endpoints, time to conception and rates of clinical pregnancy,
miscarriage, and ectopic pregnancy are measured 30 weeks after receiving
allocated treatment. In all women that fail to conceive within this
timeframe, a second-look hysteroscopy will be scheduled within 2 to 6
weeks to check for IUAs.
The long-term follow-up starts if the patient is pregnant, within 30 weeks

after receiving allocated treatment. Women will be contacted every
120 | CHAPTER 8
trimester. An overview of the collected data is shown in supplement 2.
Figure 1
Trial flow chart for a randomised controlled trial of anti-adhesion gel versus no gel following operative
hysteroscopy in women who wish to conceive. IUAs, intrauterine adhesions; RPOC, retained products of
conception; OI, Ovulation induction; COS, controlled ovarian stimulation; US, ultrasound.
Statistical analysis 8
Continuous variables will be summarised with descriptive statistics (mean
and standard deviation for data that are approximately normally distributed
and median and interquartile range (IQR) otherwise). Categorical data will
be presented as frequency and percentage.
The primary endpoint, conception leading to live birth 30 weeks after

randomisation, will be analysed using binary logistic regression taking centre
and type of pathology into account. The estimated OR with 95% CI will be
reported.
CHAPTER 8 | 121
The secondary endpoint, time to conception, will be analysed using
Kaplan-Meier analyses and randomisation groups will be compared using
a Cox model adjusting for centre and type of pathology. The intervention
effect will be expressed as a hazard ratio (HR).
The secondary endpoints, clinical pregnancy, miscarriage, ectopic pregnancy
and IUA rates, will be analysed similarly as the primary endpoint. Whereas
the variables describing the course of pregnancy will be expressed as OR or
mean difference (MD).
The primary analysis will be the intention-to-treat analysis (ITT) analysis.

All participants will be included in the analysis in the groups to which they
were originally assigned, regardless of what subsequently occurred.
Multivariate imputation by fully conditional specification (FCS) will be used
for outcome data that are missing (36). The predictors used for the
imputation model will be randomisation group, centre, intended mode of
fertility treatment, change in fertility treatment (yes/no), type of pathology
treated by operative hysteroscopy, age of the participant, weight and height
of the participant, duration of infertility, type of infertility (primary or
secondary), cause of infertility (ovulatory disorder, male factor, tubal factor,
unexplained, endometriosis) and smoking (yes/no).
Two sensitivity analyses will be performed. First, ITT with non-response

imputation. Second, a per protocol (PP) analysis, excluding all women in
the ITT population who no longer wish to conceive, who have an incomplete
follow-up or who received a treatment different from the randomised group.
Two subgroup analyses will be performed. First, to explore whether the

effect of ACP gel on the primary endpoint might differ between types of
pathology. This analysis is similar to that of the primary endpoint and
stratification factor ‘type of pathology treated by hysteroscopy’ will be
added as a categorical predictor variable. An interaction term between
type of pathology and randomisation group will be included in the model.
Second, two scenarios are considered: no change in fertility treatment and
change in fertility treatment. These analyses are similar to that of the
primary endpoint. All subgroup analyses will be performed both on the ITT
and the protocol-compliant sample.
Statistical analyses will be performed with the use of SAS (SAS Institute,
Cary, NC, USA) and R (R Core Team, 2019).
Sample size
Sample size calculation for the logistic regression on the primary endpoint
was performed in SAS version 9.4 using the power procedure.
The alternative hypothesis states that the proportion of pregnancies leading
to live birth at 30 weeks after randomisation is 45% in the control group
(no ACP gel) and 60% in the intervention group (ACP gel).
The sample size analysis was based upon our own database regarding the
122 | CHAPTER 8
pregnancy rate after operative hysteroscopy performed from 2011 until
2016. Based on these data, a pregnancy rate of 45% was expected in the
control group. The pregnancy rate for the intervention group was expected
to be 60%. This percentage is based on expert opinion in combination with
the pregnancy rate seen in a subgroup of single / lesbian women and male
infertility in the same database.
Based upon the Belgian Register for Assisted Procreation (BELRAP database),
the cumulative clinical pregnancy rate after 6 intrauterine inseminations
and 3 embryo transfers was 47% and 46.5% respectively, regardless of age.
We need 399 participants to achieve 85% power at a significance level of 5%,

to demonstrate or refute an increase from 45% to 60%. We expect a drop-out
rate of maximum 10% after randomisation leading to a sample size of 444
participants that should be randomised.
Sample size analysis per pathology was not performed because of the
pragmatic design.
DISCUSSION
Operative hysteroscopy to treat intrauterine pathologies is a frequently

performed procedure in women wishing to conceive. Following the
procedure, IUAs may develop and this may compromise women’s fertility
prognosis.
A Cochrane systematic review on the effectiveness of anti-adhesion methods

following operative hysteroscopy in women wishing to conceive, to improve
key reproductive outcomes or to decrease IUAs has shown that the quality of
evidence was low (18).
The Prevention of Adhesions Post Abortion (PAPA) trial is the largest multi-
centre RCT comparing the application of ACP gel after dilation and
curettage (D&C) for miscarriage with no treatment in a population at risk
for IUAs (defined as at least one D&C in the history) (37). The IUA rate was
significantly lower in the ACP group compared to the control group.
Moreover, the mean adhesion score and the amount of moderate to severe
IUAs, assessed by the AFS scoring system, were significantly lower after the 8
application of ACP gel. Thus, ACP gel may be of benefit in a specific
subgroup of women scheduled for D&C for miscarriage with at least one D&C
in the history.
The authors have recently reported the long-term follow-up, including

fertility and obstetrical outcomes of the women who participated in the
PAPA trial (38). Questionnaires were sent 3, 6 and 12 months after D&C.
The rates of pregnancy, miscarriage and live birth, and time to conception
CHAPTER 8 | 123
were not statistically different. However, this trial has some important
limitations. First, the study was not powered for reproductive outcomes.
Second, second-look hysteroscopy revealed more IUAs in the control group,
and these were removed because it was considered to be unethical not to
perform hysteroscopic adhesiolysis.
Currently, in Belgium, anti-adhesion gels are only partially reimbursed in

specific conditions (< 40y, wishing to conceive, scheduled for laparoscopy or
laparotomy) and there is no reimbursement for the use in hysteroscopy.
The AGNOHSTIC trial aims to provide the evidence that a decrease in IUA
formation by application of ACP gel following operative hysteroscopy,
improves reproductive outcomes in women wishing to conceive. If the
AGNOHSTIC trial succeeds, we plan to perform a health-economic analysis in
order to emphasize the need for reimbursement. This will be the topic of a
separate publication.
This study has some important strengths. To our knowledge, this is the first
large multicentre and well-designed RCT focusing on the influence of ACP
gel on reproductive outcomes. Our study is powered to detect a difference
in the primary study outcome, conception leading to live birth, measured
at a fixed time point, namely 30 weeks after randomisation. Measuring ‘live
birth’ as primary endpoint would imply a longer follow-up period and a risk
of multiple outcomes in one patient, different modes of conception per
patient and risk of drop-out. It would make the design of this pragmatic trial
more complicated.
Moreover, women will be well monitored during the short-term follow-up by
monthly contact and every trimester during long-term follow-up instead of
using questionnaires which may be accompanied by recall bias.
Furthermore, patient representatives are involved and will participate to
the trial steering committee (TSC).
This study also has some limitations. Our study population will be a mix of
women trying to conceive by regular sexual intercourse or fertility
treatment. This composition was chosen because of the pragmatic character
of our study, to meet the recruitment options of all the involved centres,
and to reach our large sample size in an acceptable time period.
Women will be included until the age of 47 and it is known that age is an
important predictor for fertility. The present study uses the stratified
randomization method. However, age is not included as a covariate.
Although, this is a pragmatic study and the Belgian law allows transfer
of frozen embryos until 47 years. The bottom line of the trial is to study
whether the application of ACP gel subsequent to operative hysteroscopy in
women wishing to conceive improves their reproductive outcome.
Co-treatment with hormonal medication may be given or repeated SIS or
hysteroscopy may be scheduled for sever IUAs, according to the standard
practice of the participating centre. Thus, it is prevented that women with
severe IUAs allocated to the control group do not receive a postoperative
anti-adhesion treatment.
124 | CHAPTER 8
Three to 6 weeks after the operative hysteroscopy with complete pathology
removal, women may be scheduled for second-look hysteroscopy,
according to local practices. IUAs on second-look hysteroscopy will be
treated by adhesiolysis. This may impact the primary outcome in favour of
the control group. However, both issues, additional anti-adhesion treatment
and adhesiolysis, will be solved because stratification is done per centre and
pathology.
Lastly, to be in line with the CONSORT guidelines, the primary endpoint will
be measured at a pre-specified time point, namely 30 weeks after
randomisation. Only if the intrauterine pathology is completely removed,
the allocated treatment will be announced and applied. Otherwise, women
are scheduled for a second operative hysteroscopy followed by the allocated
treatment. Thus, their timeframe to become pregnant will be shorter.
CHAPTER 8 | 125
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128 | CHAPTER 8
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CHAPTER 8 | 129
CHAPTER 9
General discussion
132 | CHAPTER 9
PAIN RELIEF IN OFFICE DIAGNOSTIC HYSTEROSCOPY:
IS IT BETTER TO TAKE A PAINKILLER, AND WHICH ONE?
In our pilot study, pain relief and success rates for office diagnostic
hysteroscopy were not significantly different between nifedipine, naproxen
and placebo. Nifedipine was associated with more, albeit tolerable,
side-effects. Our study was limited by the small sample size, the lack of a
sample calculation, the performance of hysteroscopic procedures and the
administration of medication outside the defined timeframe in some
women, and the performance of additional procedures in some women.
Nifedipine for pain relief in office hysteroscopy was not yet studied before.
Recently, a Cochrane review has been published on the use of nifedipine for
pain relief in primary dysmenorrhea, which is the only gynecologic
indication so far (91). Compared to placebo, nifedipine was effective for
pain relief.
The literature regarding pain relief in office diagnostic and operative
hysteroscopy has expanded since the start of our study. The evidence for
analgesia (NSAIDs, opioids, antispasmodic and Transcutaneous Electrical
Nerve Stimulation (TENS)), compared to no treatment, placebo, another or
a different dose/scheme analgesic or anesthetic, has been examined by
De Silva and colleagues (92). NSAIDs reduce pain during and after the
hysteroscopic procedures without an increase in side-effects. The authors
conclude that women without contraindications should be advised to take
oral NSAIDs before the hysteroscopic procedure, although the optimal route,
dose and timing of administration has yet to be determined. TENS could
serve as an alternative to NSAIDs in case of contraindications. However,
TENS entails logistical challenges when performed for office hysteroscopy.
A major limitation of this meta-analysis is the methodologic and clinical
heterogeneity of the studies included. Hence, we believe more good quality
data are needed before one can recommend NSAIDs routinely.
Based on the current findings NSAIDs may be considered, however, we
cannot advise it routinely for office diagnostic hysteroscopy.
WHAT IS THE VALUE OF MECHANICAL HYSTEROSCOPIC TISSUE

REMOVAL SYSTEMS IN THE REMOVAL OF FIBROIDS?
The mechanical hysteroscopic tissue removal system (Truclear™ ultra plus)

was faster than bipolar electrosurgery (26 Fr.) for the removal of smaller
(up to 3 cm) submucous type 0 and 1 fibroids. This could be explained by the
simultaneous cutting and aspiration effect under direct visual control with
immediate removal of the resected tissue. Although, the median
operating time of both techniques was relatively short, and with a longer
median instrumentation setup time in the mechanical hysteroscopic tissue 9
resection group, the difference in overall procedure time did not reach
statistical significance.
Our study is the first RCT focusing on type 0 and 1 submucous fibroids. Other
CHAPTER 9 | 133
studies have compared these two techniques in women with polyps and
fibroids or in a sample including submucous type 2 fibroids (14,15,93–95).
Contradictory with previous RCTs using the same instrumentation setup to
remove polyps and RPOC with the mechanical hysteroscopic tissue removal
system, we observed a longer setup time in this group (30,96). Simplifying
the instrumentation setup for mechanical hysteroscopic tissue removal
systems may further reduce the time needed to perform the entire
procedure. Moreover, this variable was not reported in other trials.
Furthermore, with an increasing interest in the office setting, the resection
time is the most important amongst the time variables. It is shown that
hysteroscopic procedures (polypectomy, septum resection and endometrial
ablation) using mechanical, smaller and quicker devices are less painful in
an office setting (97). The feasibility of office hysteroscopic fibroid removal
has been reported, but small diameter instruments were used (49,98–100).
Calcified fibroids are a limiting factor for the technique of mechanical

hysteroscopic tissue removal and conversion to bipolar electrosurgery was
necessary in two cases. Still, there was an incomplete resection. Besides,
there is a hypothetical risk that fibroid hardness may cause the loop to
break.
Submucous type 2 fibroids seem to be challenging for both techniques. The

size of the intramural component is an independent predictor for complete
fibroid removal using mono- and bipolar electrosurgery (101).
The presence of submucous type 2 fibroids in our trial, although it was an
exclusion criterion, is an important limitation. The preoperative fibroid
classification seems to be difficult. The recent published guideline regarding
hysteroscopic fibroid removal of the International Society for Gynecologic
Endoscopy (ISGE) recommends performing a saline infusion sonography (SIS)
and / or a diagnostic hysteroscopy in the diagnostic work-up and to use the
STEPW classification, a scoring system based on size, topography, extension
of the base, penetration and lateral wall, as predictor for complete removal
and complications (102,103).
Three adverse events were encountered in the mechanical hysteroscopic

tissue removal group (one after conversion to electrosurgery), whereas
there were none in the bipolar electrosurgery group. In contrast, the data
from the Manufacturer and User Facility Device Experience (MAUDE)
database show that in general complications such as fluid overload, uterine
perforation and bleeding do occur with electromechanical hysteroscopic
tissue removal, albeit less frequently compared to electrosurgery (104).
Currently, the ISGE guidelines recommend the mechanical hysteroscopic

tissue removal system for the resection of submucous type 0 fibroids. For
submucous type 1 and 2 fibroids there is a lack of high-quality data, hence
electrosurgery is recommended until new good quality studies appear. Our
RCT provides evidence for using mechanical hysteroscopic tissue removal of
submucous type 1 fibroids.
134 | CHAPTER 9
WHAT ABOUT MANUALLY DRIVEN HYSTEROSCOPIC TISSUE REMOVAL
DEVICES, ARE THEY A SUITABLE ALTERNATIVE FOR POLYPECTOMY?
We performed the first clinical evaluation of a manually driven

hysteroscopic tissue removal device (Resectr™) for polypectomy.
In a RCT we examined whether the manually driven hysteroscopic tissue

removal device (Resectr™ 9 Fr.) was non-inferior to an existing motor driven
system (Truclear™ incisor mini).
The simplified instrumentation, which is associated with the manually driven
system, was non-inferior to the motor driven system. The advantage is the
‘plug and play’ design, whereas the motor driven system is characterized by
operator-controlled settings (action mechanism and window lock).
Nevertheless, the instrumentation setup of the manually driven device could
be further simplified through replacement of the aspiration pump by a
vacuum wall source or an integrated vacuum system. The median reported
instrumentation setup times of mechanical hysteroscopic tissue removal
systems, in RCTs using the same definition, were higher (30,96,105).
The total procedure time for hysteroscopic polypectomy with both devices
was also non-inferior, but the resection time was inconclusive. The Resectr™
9 Fr. is equipped with a larger working window (7.5 mm) than the Truclear™
incisor mini (5 mm), which could have resulted in shorter resection times.
However, inconsistent activation of the handpiece might result in variable
resection speeds. Notwithstanding, the resection times were low, which is
important with the increasing interest in the office setting. The reported
resection times of motor driven systems were not comparable to our
measures because of heterogeneity in terms of polyp size and number
(16,106).
The presence of fibroids and fundal polyps appeared to be challenging for

both techniques. The Resectr™ was not designed to remove dense tissue
such as fibroids. Some of the motor driven systems have specific devices to
resect fibroids (dense tissue shaver mini and plus device (Medtronic),
MyoSure XL device (Hologic)). Fundal polyps may be hard to reach.
Therefore, other brands (Hologic and Storz) have developed devices adapted
to reach the fundal region.
Surgeons felt comfortable with the instrument in both groups, but results
were in favor of the motor driven hysteroscopic tissue removal system.
The clinical relevance is questionable, but a possible explanation is the
necessity of repetitive movements of the hand. Therefore, polyps should not
be too large, but the optimal size is yet to be determined.
Adverse events did not occur, and patient’s satisfaction did not differ
significantly between the two techniques. 9
In a prospective cohort study, we assessed the feasibility of the manual
hysteroscopic tissue removal device (Resectr™ 5 Fr.) to remove small polyps
CHAPTER 9 | 135
in an office setting without any anesthesia.
The Resectr™ 5 Fr. complies with its characteristics (mechanical energy,
small diameter, and fast procedure) to the recommendations of Da Silva et
al to reduce pain when performing office hysteroscopy (97). Another
advantage is that the device is compatible with the 5 Fr. working channel of
any operative hysteroscope, and with the simplified instrumentation setup it
is suitable for the ‘see and treat’ approach.
The median installation setup time and time to complete polyp removal
were low. The reported installation setup times associated with the existing
motor driven tissue removal systems were higher (30,96,105). Our resection
time was incomparable with those reported in the literature using other
hysteroscopic instruments because of heterogeneity in time definitions,
polyp sizes and polyp numbers(13,16,107–114).
The surgeon reported outcomes about the instrument use in an office

setting were good. This is in line with reported scores considering the use
of electromechanical hysteroscopic tissue removal systems in the office
(15,115,116).
Women reported low pain scores. The reported pain scores in literature
using other hysteroscopic instruments in an office setting are heterogeneous
in terms of measure point (during or after the procedure) and measure scale
(10-point Visual Analogue Scale (VAS) or 100-point VAS scale).
Adverse events did not occur, and women’s satisfaction was high and
comparable with those reported in literature for office polypectomy using
electromechanical hysteroscopic tissue removal systems (112,114).
The major limitation of our trial was the unstandardized use of pain
medication, the inclusion of only smaller polyps (≤ 8 mm) and the lack of a
control group. The concomitant use of pain medication could have
influenced our results. Nevertheless, this corresponds with the reality in
clinical practice and no procedure had to be discontinued because of pain.
The small polyp size was chosen because this corresponds with the
diameter of the internal cervical ostium which is within the feasible range
of 5 Fr. mechanical instruments. The latter could be a control group in
future research. Whether such RCT is worth the effort was, in accordance
with the IDEAL framework (Idea, Development, Exploration, Assessment,
Long-term study), evaluated through this feasibility study.
Summarized, the Resectr™ 9 Fr. could be considered for polypectomy in

select cases, whereas the Resectr™ 5 Fr. could be useful in the office
setting.
136 | CHAPTER 9
CAN WE LIMIT THE RISK OF IUA FORMATION AFTER OPERATIVE
HYSTEROSCOPY AND THEREBY IMPROVE REPRODUCTIVE OUTCOMES?
In a follow-up study of women with RPOC treated by hysteroscopy,

comparing mechanical tissue removal with loop resection, it appears there
is no detrimental impact on fertility. Reproductive outcomes after
mechanical hysteroscopic tissue removal of RPOC were not yet studied
before, but data were available for loop resection. The clinical
pregnancy rate in our study was in accordance with those reported in
literature and higher than 80% (32,117). Although not significantly different,
the live birth rate in the mechanical hysteroscopic tissue removal group
(88.9%) was higher than in the loop resection group (68.2%). The reported
live birth rates after hysteroscopic removal of RPOC in literature were 80%
and more (32,117). In the loop resection group, the miscarriage rate was in
line with the prevalence in the general population and those reported in
literature (32). We found a short time to conception, whereas the reported
intervals are usually larger, but there is inconsistency in definition (118–
123).
Remarkably, placental complications occurred in around 1 in 5 women in

both groups. Ben-Ami et al reported placental complications in 13.3% of
the pregnancies after loop resection of RPOC (120). Unfortunately, further
details were not provided. Ikhena et al showed placental complications in
18.1% of the pregnancies after hysteroscopic RPOC removal using 5 Fr.
mechanical instruments and mechanical hysteroscopic tissue removal
systems (122). Placental complications were defined as placenta accrete,
placenta previa and retained placenta. Smorgick et al reported RPOC in
11.9%, and third stage of labor placental complications in 23.9% of the
subsequent pregnancies after hysteroscopic RPOC removal using 5 Fr and 13
Fr. mechanical instruments (124).
It is hypothesized that the presence of RPOC may itself be a contributor to

subsequent IUA formation due to inflammation and infective effects (125).
Ben-Ami et al showed in a retrospective study of women with RPOC treated
by D&C or hysteroscopy, worse reproductive outcomes when the diagnosis
was confirmed on pathology analysis. Moreover, the initial RCT on which our
follow-up study is based, showed IUAs in only 3% in both groups (30). Again,
placental complications may be related to the history of retained products,
rather than the surgical technique.
Our study was limited by its retrospective design, the related missing data,
although the response rate was high (80.2%), the risk of recall bias, and the
lack of a power analysis for reproductive outcomes. In roughly one-third of
the initial study population the diagnosis was not confirmed by pathology
analysis. This highlights the difficulty of diagnosing RPOC.
9
Standardized criteria for the definition of, and when to evaluate RPOC are
lacking. A review of the diagnostic criteria for RPOC after miscarriage or
CHAPTER 9 | 137
induced abortion revealed that an ultrasonographic endometrial thickness of
15 mm or more 2 weeks after the primary treatment were most often used
(126).
Although the superiority of hysteroscopic RPOC removal over D&C has still
to be determined, the hysteroscopic approach seems promising in terms of
reproductive outcome.
Hooker et al has performed major research in the field of adhesion

prevention after D&C. Anti-adhesion gel, compared to no gel, after D&C in
women at risk for IUAs (at least one D&C in history) significantly decreased
the IUA rate (127). The reproductive outcome of women pursuing a
pregnancy at 12 months follow-up was not significantly different, whereas
ongoing pregnancy and live birth rate at 42 months follow-up was in favor of
the intervention group (128,129). A major limitation of these studies is that
they were powered for IUAs and the use of questionnaires to study
reproductive outcomes.
Since the Cochrane review from Bosteels et al in 2017, which assessed the
effectiveness of anti-adhesion therapies following operative hysteroscopy
for treatment of female subfertility, there have been a number of new
publications, and an update is urgent (84). However, there is still a small
number of trials reporting on reproductive outcomes. Some new reviews
of varying quality and added value have been published. Unanyan et al
showed, based on 4 RCTs, improved pregnancy rates after D&C or
hysteroscopic adhesiolysis using anti-adhesion gel compared to an IUD or
no treatment(130). Korany et al proved, based on 3 RTCs, higher pregnancy
rates after hysteroscopic adhesiolysis using intrauterine platelet-rich plasma
compared to no treatment (131). Platelet-rich plasma contains an
autologous concentration of platelets as well as growth factors
promoting tissue healing and regeneration. However, the disadvantages are
the requirement of a processed blood sample, the limited action time as the
growth factors are released during 15 minutes after the preparation, the
liquidity at room temperature and consequently the poor barrier properties.
Fei et al stated, based on 2 retrospective studies, that the pregnancy rate
did not improve significantly using anti-adhesion gel compared to no gel
after hysteroscopic adhesiolysis (132). Zeng et al showed, based on 2 RCTs,
improved pregnancy rates when using anti-adhesion gel compared to no gel
after intrauterine surgery (133).
Hence, thorough research, powered for reproductive outcome is needed.

Therefore, the AGNOHSTIC trial was designed, which is the first large
multicenter RCT focusing on the influence of anti-adhesion gel on
reproductive outcomes after operative hysteroscopy.
The primary outcome of the AGNOHSTIC trial is conception leading to live
birth, measured at a fixed time point, namely 30 weeks after randomization.
Measuring ‘live birth’ as primary outcome would imply a longer follow-up
period, a risk of different modes of conception and multiple outcomes in
138 | CHAPTER 9
one patient, and risk of drop-out. Participants are contacted every month
during the short-term follow-up and every trimester during the long-term
follow-up to reduce recall bias, which is accompanied using questionnaires.
Moreover, participants, gynecologist’s performing the
hysteroscopic procedures and fertility physicians are unaware of the
treatment allocation and sterile ultrasound gel is used as placebo. The study
is limited by the composition of the study group (mix of regular sexual
intercourse and fertility treatment) and the inclusion of women up to 47
year to meet the pragmatic character of the study.
Currently, in Belgium, anti-adhesion gels are only partially reimbursed in

specific conditions (< 40 years, wishing to conceive, scheduled for
laparoscopy or laparotomy) and there is no reimbursement for the use in
hysteroscopy.
IMPLICATIONS FOR CLINICAL PRACTICE

- Pain relief might not always be necessary.
- If pain relief is necessary, an NSAID could be considered. Timing of
administration should be in accordance with Tmax.

- Preoperative diagnosis is key to select the best instrumentation for
operative hysteroscopy.
- The use of STEPW classification of submucous fibroids is recommended to
predict the complexity of the hysteroscopic procedure.
- Hysteroscopic removal of type 0 and 1 submucous fibroids are faster using
the mechanical hysteroscopic tissue removal system, compared to
conventional bipolar electrosurgery.
- The manually driven hysteroscopic tissue removal device could serve as
an alternative for the existing motor driven devices to resect polyps.
- The small diameter variant of the manually driven hysteroscopic tissue
removal device is feasible in an outpatient setting, without anesthesia.
- An overview of the hysteroscopic instruments and their indications is
provided in Figure 7.

- Hysteroscopic treatment of RPOC, comparing mechanical hysteroscopic
tissue removal device with hysteroscopic loop resection, is not
CHAPTER 9 | 139
Figure 7 Overview of the hysteroscopic instruments and their indications
140 | CHAPTER 9
detrimental for reproductive outcomes, but around 20% of the subsequent
pregnancies are characterized by placental complications.
IMPLICATIONS FOR RESEARCH

The necessity of pain relief should be determined in a well-designed double
blinded RCT, comparing NSAIDs and placebo. Naproxen is commonly used.
It is long working (Tmax 2-4 hours, T1/2 10-17 hours) with the highest risk on
gastro-intestinal side-effects, while the risk on cardio-vascular side-
effects is low. Ibuprofen should be investigated in future research. It is short
working (Tmax 1-2 hours, T1/2 2 hours) with a lower risk on gastro-intestinal
side-effects, and a low risk on cardio-vascular side-effects provided that
low doses are used. The advantage of (oral) analgesia with a quick onset of
action is that it is easier to incorporate into daily practice. Consequently,
the timing of administration can be better predicted.
If the superiority of NSAIDs is proven, non-inferiority studies focusing on
alternatives could be designed.
Diagnostic and operative hysteroscopic procedures without the need for
cervical dilation, performed in an outpatient setting should be analyzed
separately. Other strategies to maximize patients’ comfort should be
considered (vaginoscopy, saline as distension medium and low distention
pressure).

The value of mechanical hysteroscopic tissue removal systems as an
alternative to conventional bipolar electrosurgery for the removal of type
2 submucous fibroids needs to be determined. The study design described
in chapter 4 can be used. Diagnosis and classification of type 2 submucous
fibroids could be a pitfall. It is important that this is done carefully.
The manually driven hysteroscopic tissue removal device should be further
explored in terms of maximum polyp size suitable for resection and other
indications (targeted biopsy and RPOC). Comparative studies between the
small diameter variant of the manually driven device and 5 Fr. mechanical
and 5 Fr. bipolar instruments for polypectomy needs to be performed.
Currently, we are conducting a follow-up study of two RCTs (mechanical
hysteroscopic tissue removal versus bipolar electrosurgery, and manually
driven versus motor driven hysteroscopic tissue removal) considering
recurrence of AUB and polyps (NCT05337046, NCT05337605).
The mechanical hysteroscopic tissue removal device itself could be subject
to improvement: adaptation of the tip to reach the fundal region or the
intramural part of a fibroid, an integrated vacuum system,
a non-disposable variant, a small diameter scope without compromising the
instrument diameter.
9
In general, in the Belgian healthcare system, the characteristics of the
outpatient setting in terms of intrauterine pathology, equipment, staff and
finance, should be elaborated.
CHAPTER 9 | 141
Finally, if well-conducted research in the field of hysteroscopy proves the
effectiveness of treatments, cost-effectiveness analyses should be
performed.
Part III Reproductive outcome after operative hysteroscopy.

An update of the Cochrane review on antiadhesion therapy following
operative hysteroscopy for treatment of female subfertility is urgently
needed.
The recruitment period of the AGNOHSTIC trial ends December 2023.
A first analysis is to be expected mid-2025. If the application of antiadhesion
gel compared to no gel, following operative hysteroscopy in women
wishing to conceive increases the chance of conception leading to live birth,
a health-economic analysis will be planned.
CONCLUSIONS
Hysteroscopy is a widely used and important method in the diagnosis and

treatment of AUB and in the fertility work-up. Nevertheless, there are still
some aspects left for improvement. In this thesis we explored innovations
that could improve hysteroscopic practice.
The role of pain relief in office diagnostic hysteroscopy is uncertain.
The mechanical hysteroscopic tissue removal system is faster than bipolar
resection to remove type 0 and 1 submucous fibroids up to 3 cm.
The manually driven hysteroscopic tissue removal device is non-inferior to
the motor driven system, and it can be considered for polypectomy in select
cases. The small diameter variant of the manually driven device could be
useful in the office setting. Hysteroscopic treatment of RPOC is not
detrimental for reproductive outcomes. Whether anti-adhesion gel after
operative hysteroscopy in women wishing to conceive is beneficial for
reproductive outcomes has yet to be proven.
142 | CHAPTER 9
9
CHAPTER 9 | 143
144 |
SUMMARY
Hysteroscopy is an important method for diagnosis and treatment of intra-

uterine pathology. It is performed to investigate the origin of AUB, to
elucidate abnormal findings seen on other imaging exams or in the fertility
work-up.
The technique of hysteroscopy has evolved over the years. Currently, there
is a preference for small diameter instruments using mechanical energy and
for performing hysteroscopic procedures in the office setting.
In this thesis we explored innovations that could improve hysteroscopic
practice.
Pain relief is a strategy that has emerged to maximize patient comfort

during office hysteroscopy (part I).
The pilot RCT in Chapter 3 showed that the role of analgesia in office
diagnostic hysteroscopy is uncertain. Based on the current findings NSAIDs
may be considered, however, we cannot advice it routinely. Nifedipine for
pain relief in office hysteroscopy was not yet studied before and it was
associated with more, albeit tolerable, side-effects.
Mechanical hysteroscopic tissue removal systems have been developed to

avoid the use of electrosurgery and to prevent a poor vision because of
swirling tissue chips (part II). Meta-analyzes had been performed comparing
the mechanical hysteroscopic tissue removal systems with electrosurgical
resection (5 Fr bipolar electrodes and the resectoscope) for the removal of
polyps and type 0 and 1 submucous fibroids. The mechanical hysteroscopic
tissue removal system is associated with a shorter operating time and more
complete resections. Subgroup analysis per pathology, however, showed
only a benefit for the removal of polyps. Nevertheless, these meta-analyzes
have some shortcomings (limited number of studies, polyps and fibroids have
different tissue characteristics relating differently to the uterine cavity,
various brands and diameters of devices were included with possibly
other resection rates, 5 Fr bipolar electrodes and the resectoscope involve
a different technique, and lastly the primary outcome, operation time, had
different definitions).
The RCT in Chapter 4 provided the evidence for the use of a mechanical
hysteroscopic tissue removal system (Truclear™ ultra plus), compared to
bipolar electrosurgery (26 Fr.), to remove type 0 and 1 submucous fibroids.
However, calcified fibroids are challenging in both techniques. Currently, the
ISGE guidelines recommend the mechanical hysteroscopic tissue removal
system for the resection of submucous type 0 fibroids. For submucous type
1 and 2 fibroids there is a lack of high-quality data, hence electrosurgery is
recommended until new good quality studies appear. Our RCT provided the
evidence for mechanical hysteroscopic tissue removal of submucous type 1
fibroids.
| 145
The development of devices continued and a new manually driven
hysteroscopic tissue removal device for polypectomy became available in 2
sizes (Resectr™ 5 Fr. and 9 Fr.). We performed the first clinical evaluation of
these manually driven hysteroscopic tissue removal devices.
Chapter 5 showed the non-inferiority of the manually driven (Resectr™ 9 Fr.)
compared to an electromechanical driven system (Truclear™ incisor mini)
for the removal of polyps in terms of installation setup and total procedure
time. The resection time was inconclusive. However, surgeons are more
convenient with the electromechanically driven system, leaving the manual
device for select cases of hysteroscopic polypectomy.
Chapter 6 showed the feasibility of the small diameter manual
hysteroscopic tissue removal device (Resectr™ 5 Fr.) for polypectomy in an
office setting without any anesthesia. This is an important finding with the
growing interest in the office setting. However, the lack of a control group is
a major limitation, which could be the next step in future research.
Several intrauterine pathologies, including endometrial polyps, fibroids with

uterine cavity deformation, uterine septa, RPOC and IUAs have been linked
with female fertility problems. The evidence in favor of operative
hysteroscopy for improving reproductive success is sparse and of moderate
to low quality. Nevertheless, hysteroscopy is very often performed,
especially in women attending fertility clinics because among the medical
community the presence of intrauterine pathology distorting the uterine
cavity is widely believed to impair reproductive outcome. The formation
of IUAs following operative hysteroscopy is a long-term consequence with
negative impact on reproductive success (Part III).
Hysteroscopy is a recent approach of RPOC. The follow-up study of women

treated for RPOC by hysteroscopy (Truclear™ incisor plus versus loop
resection) in Chapter 7 showed that there appears to be no detrimental
impact on the reproductive outcome. Remarkably, around 20% of the
subsequent pregnancies are characterized by placental complications.
However, the latter may be related to the placental remnants, rather than
the surgical technique.
Anti-adhesion methods are a hot topic. A Cochrane review in 2017

demonstrated that the use of anti-adhesion gel following operative
hysteroscopy may decrease the occurrence of IUAs at second look
hysteroscopy compared to no treatment or placebo. However, there are a
small number of trials reporting on reproductive outcomes.
The application of anti-adhesion gel following D&C, in women with at least
one previous D&C, seems to have a favorable effect on subsequent
reproductive outcomes, compared with no treatment. Hence, thorough
research in the field of hysteroscopy, powered for a reproductive outcome
is needed. Therefore, the AGNOHSTIC trial was designed, which is the first
large multicenter RCT focusing on the influence of anti-adhesion gel on
reproductive outcomes after operative hysteroscopy. Chapter 8 presents
the protocol of this ongoing trial. Currently, in Belgium, anti-adhesion gels
146 |
are only partially reimbursed in specific conditions (< 40 years, wishing to
conceive, scheduled for laparoscopy or laparotomy) and there is no
reimbursement for the use in hysteroscopy.
| 147
148 |
SAMENVATTING
Een hysteroscopie is een kijkonderzoek waarbij een camera via de vagina en

de baarmoederhals in de baarmoederholte wordt gebracht. Een aandoening
in de baarmoederholte (intra-uteriene afwijking) kan op deze manier
gediagnosticeerd en behandeld worden. Een hysteroscopie wordt verricht
voor de uitwerking van abnormaal uterien bloedverlies, afwijkende beeld-
vormingsonderzoeken of
fertiliteitsproblemen.
De hysteroscopische techniek is geëvolueerd naar het gebruik van
instrumenten met een smalle diameter en mechanische energie, en kan
verricht worden op de polikliniek. Bovendien is er meer aandacht voor het
voorkomen van intra-uteriene adhesies, een langetermijngevolg van een
operatieve hysteroscopie, die een impact kan hebben op de fertiliteit.
In deze thesis onderzochten we innovaties die de hysteroscopische
praktijkvoering zou kunnen optimaliseren.
Het gebruik van pijnstilling tijdens een poliklinische hysteroscopie zou een
gunstige invloed kunnen hebben op het comfort van de patiënten (deel 1).
De piloot RCT in Hoofdstuk 3, waarin nifedipine werd vergeleken met

naproxen of placebo, toonde aan dat er onduidelijkheid is over de rol van
pijnstilling tijdens een poliklinische diagnostische hysteroscopie.
Niet steroïdale anti-inflammatoire middelen (NSAIDs) kunnen overwogen
worden, maar of we dit standaard moeten aanbevelen is onduidelijk.
Het gebruik van nifedipine, een bloeddrukverlagend middel dat als
nevenwerking de baarmoeder ontspant, als pijnstilling voor een
poliklinische diagnostische hysteroscopie werd nog niet eerder bestudeerd.
Uit deze piloot RCT blijkt dat het geassocieerd is met meer, weliswaar
dragelijke, bijwerkingen.
Mechanische hysteroscopische weefselverwijderingssystemen zijn

ontwikkeld om het gebruik van elektrochirurgie te vermijden en om een
betere visualisatie te hebben doordat weefselfragmenten onmiddellijk
worden verwijderd (deel 2). Meta-analyses vergeleken het mechanisch
hysteroscopisch weefselverwijderingssysteem met elektrochirurgie (5 Fr.
bipolaire elektroden en de resectoscoop) voor het verwijderen van poliepen
en myomen. Het mechanisch hysteroscopisch weefselverwijderingssysteem
is sneller en resulteert in meer complete resecties. Subgroep analyse per
pathologie toont echter enkel een voordeel voor het verwijderen van
poliepen. Deze meta-analyses hebben weliswaar enkele belangrijke
tekortkomingen.
De RCT in Hoofdstuk 4 toonde aan dat het mechanisch hysteroscopisch

weefselverwijderingssysteem, vergeleken met de bipolaire resectoscoop,
sneller is voor het verwijderen van type 0 en 1 submucosale myomen.
Verkalkte myomen waren echter een uitdaging voor beide technieken.
| 149
De ‘International Society for Gynecologic Endocscopy’ (ISGE)-richtlijnen
bevelen momenteel het mechanisch hysteroscopisch
weefselverwijderingssysteem aan voor het verwijderen van type 0
submucosale myomen. Elektrochirurgie wordt aanbevolen voor type 1 en
2 submucosale myomen omwille van het ontbreken van goed onderbouwd
onderzoek. Onze studie ondersteunt het gebruik van het mechanisch
hysteroscopisch weefselverwijderingssysteem voor het verwijderen van type
1 submucosale myomen.
Het mechanisch hysteroscopisch weefselverwijderingssysteem is nu ook

beschikbaar in een hand-gedreven variant met 2 afmetingen (Resectr™ 5 Fr.
en 9 Fr.). Het is ontwikkeld voor het hysteroscopisch verwijderen van
poliepen. In deze thesis hebben we de eerste klinische evaluatie verricht
met het nieuwe hand-gedreven systeem.
De ‘non-inferiority’ RCT in Hoofdstuk 5 toonde aan dat de installatietijd en
de totale proceduretijd voor het hysteroscopisch verwijderen van poliepen
non-inferieur zijn wanneer het hand- (Resectr™ 9 Fr.) met het motor-
gedreven systeem wordt vergeleken. Het gebruiksgemak daarentegen is in
het voordeel van het motor-gedreven systeem. We concludeerden dat het
hand-gedreven systeem voor een hysteroscopische poliepresectie
voorbehouden is voor specifieke gevallen.
De observationale studie in Hoofdstuk 6 beschreef het gebruik van het
hand-gedreven systeem met een smalle diameter (Resectr™ 5 Fr.) voor een
poliklinische hysteroscopische poliepresectie zonder verdoving. Hoewel de
procedure haalbaar lijkt te zijn, is het ontbreken van een controlegroep een
belangrijke tekortkoming van deze studie. Deze haalbaarheidsstudie toont
aan dat volgens het ‘IDEAL framework’ (een beschrijving van de stadia in
innovatie in de chirurgie) een RCT de volgende stap is.
Intra-uteriene afwijkingen (poliepen, vleesbomen met een impact op

de baarmoederholte, tussenschotten, placentaresten en intra-uteriene
verklevingen) hebben mogelijk een invloed op de fertiliteit.
De literatuur die gunstige effecten van een hysteroscopische behandeling
van deze afwijkingen beschrijft is van matig tot lage kwaliteit. Toch wordt
de ingreep frequent verricht bij vrouwen met fertiliteitsproblemen.
We weten echter dat er zich intra-uteriene verklevingen kunnen
ontwikkelen na een operatieve hysteroscopie die op hun beurt een
negatieve invloed kunnen hebben op de reproductieve uitkomsten (deel 3).
Een placentarest is een nieuwe indicatie voor hysteroscopie. In Hoofdstuk 7

beschreven we een opvolgstudie van vrouwen die eerder hysteroscopisch
behandeld werden voor placentaresten (mechanisch hysteroscopisch
weefselverwijderingssysteem ten opzichte van lus resectie).
Beide technieken bleken geen negatieve impact te hebben op de
reproductieve uitkomsten. Placentacomplicaties (abnormale invasieve
placenta, vastzittende placenta, en placentarest) deden zich wel voor in
één op vijf zwangerschappen na een hysteroscopische
placentarestverwijdering.
150 |
Het voorkomen van intra-uteriene verklevingen is momenteel een ‘hot
topic’. Een review uit 2017 toonde aan dat het gebruik van een anti-
adhesiegel na een operatieve hysteroscopie aanleiding kan geven tot minder
adhesievorming, vergeleken met placebo of het niet gebruiken van een anti-
adhesiemethode. Er zijn echter weinig studies die reproductieve uitkomsten
rapporteren na het gebruik van een anti-adhesiemethode.
Het toedienen van een anti-adhesiegel na een curettage bij vrouwen met
minstens één curettage in de voorgeschiedenis, vergeleken met geen anti-
adhesiemethode, lijkt een gunstig effect te hebben op de reproductieve
uitkomsten In Hoofdstuk 8 werd het studieprotocol beschreven van een
multicentrische RCT waarin het aanbrengen van een anti-adhesiegel na een
operatieve hysteroscopie vergeleken wordt met geen anti-adhesie
behandeling. De uitkomst van de studie is de geboorte van een levend kind.
Inclusies in deze studie zijn lopende. Momenteel worden anti-adhesiegels in
België slechts gedeeltelijk terugbetaald in specifieke omstandigheden
(< 40 jaar, kinderwens, en laparoscopische of laparotomische ingreep). Er is
geen terugbetaling voor het gebruik bij hysteroscopische ingrepen.
| 151
152 |
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A patient-preference cohort study of office versus inpatient uterine polyp treatment for
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manufacturer and user facility device experience (MAUDE) database.
105. van Wessel S, van Vliet HAAM, Schoot BC, Weyers S, Hamerlynck TWO. Hysteroscopic
morcellation versus bipolar resection for removal of type 0 and 1 submucous myomas:
A randomized trial.
106. Noventa M, Ancona E, Quaranta M, Vitagliano A, Cosmi E, Antona DD, et al. Intrauterine
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107. Bettocchi S, Ceci O, Nappi L, Venere R Di, Masciopinto V, Pansini V, et al. Operative Office
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110. Garuti G, Centinaio G, Luerti M. Outpatient Hysteroscopic Polypectomy in Postmenopausal

Women: A Comparison between Mechanical and Electrosurgical Resection.
111. Cicinelli E, Tinelli R, Loiudice L, Loiudice I, Quattromini P, Fusco A, et al. AlphaScope vs

Lens-Based Hysteroscope for Office Polypectomy without Anesthesia: Randomized
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113. Dealberti D, Riboni F, Cosma S, Pisani C, Montella F, Saitta S, et al. Feasibility and
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116. Stoll F, Lecointre L, Meyer N, Faller E, Host A, Hummel M, et al. Randomized Study
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117. Taylor C, Ellett L, Hiscock R, Mooney S. Hysteroscopic management of retained products of

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118. Cohen SB, Kalter-Ferber A, Weisz BS, Zalel Y, Seidman DS, Mashiach S, et al. Hysteroscopy
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121. Sonnier L, Torre A, Broux P, Fauconnier A, Huchon C. Evaluation of fertility after

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126. Hamel CC, van Wessel S, Carnegy A, Coppus SFPJ, Snijders MPML, Clark J, et al.
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ABOUT THE AUTHOR
Steffi van Wessel was born on March 23, 1988 in Sint-Niklaas, Belgium. After
obtaining her high school diploma from the Berkenboom Humaniora in Sint-
Niklaas in 2006, she started her medical school at the University of Ghent.
During her last year she did research on the relationship between uterine
fibroids and fertility at the department of Obstetrics and Gynecology of the
Ghent University Hospital.
In the summer of 2013, she received her medical degree and started her
clinical career in obstetrics and gynecology. She had the opportunity to
perform general surgery in AZ Jan Palfijn Ghent for one year. Afterwards,
she was active in the department of obstetrics and gynecology of the ISALA
clinic in Zwolle (The Netherlands), the Ghent University Hospital and the
OLV clinic in Aalst. During her residency she was inspired by the scientific
work, in which she could participate, done by Prof. Dr. Steven Weyers and
Prof. Dr. Tjalina Hamerlynck.
In 2018 she graduated as a specialist in obstetrics and gynecology at the

Ghent University. She specialized in minimally invasive gynecology at the
Ghent University Hospital, where she is now member of staff. Meanwhile she
was able to setup research exploring innovations that could improve
hysteroscopic practice that finally led to this thesis.
Steffi is married to Bart Spiessens.

They are the proud parents of Julia (°2021) and Alice (°2020).
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PUBLICATIONS
Included in this thesis
van Wessel S, Rombaut J, Vanhulle A, Emanuel MH, Hamerlynck T, Weyers S. Efficacy

of oral nifedipine, naproxen, or placebo for pain relief during diagnostic
hysteroscopy in an office setting: a randomized pilot study.
J Minim Invasive Gynecol. 2023 Feb 16:S1553-4650(23)00058-4.
van Wessel S, van Vliet HAAM, Schoot BC, Weyers S, Hamerlynck TWO. Hysteroscopic
morcellation versus bipolar resection for removal of type 0 and 1 submucous
myomas : a randomized trial. Eur J Obstet Gynecol Reprod Biol. 2021;259:32–7.
van Wessel S, Hamerlynck T, van Vliet H, Schoot D, Weyers S. Manual morcellation

(Resectr™ 9fr) versus electromechanical morcellation (Truclear™) for hysteroscopic
polypectomy: a randomized controlled non-inferiority trial.
Acta Obstet Gynecol Scand. 2023;102:209-217.
van Wessel S, Hamerlynck T, van Vliet H, Weyers S, Schoot D. Clinical evaluation of a

new hand driven hysteroscopic tissue removal device, Resectr™ 5fr, for the resection
of endometrial polyps in an office setting.
van Wessel S, Coryn N, van Vliet H, Schoot BC, Weyers S, Hamerlynck T.

Reproductive and obstetric outcomes after hysteroscopic removal of retained
products of conception. J Minim Invasive Gynecol. 2020;27(4):840–6.
van Wessel S, Hamerlynck T, Schutyser V, Tomassetti C, Wyns C, Nisolle M, et al.

Anti-adhesion gel versus no gel following Operative Hysteroscopy prior to Subsequent
fertility Treatment or timed InterCourse (AGNOHSTIC), a randomised controlled trial:
protocol. Hum Reprod Open. 2021;2021(1):hoab001.
Not included in this thesis
van Wessel S, Wauters L, Weyers S, Hamerlynck T. The use of an intrauterine balloon

in preventing adhesion recurrence after hysteroscopic adhesiolysis: a feasibility
study. J Obstet Gynaecol. 2022.
D’hoore E, D’hoore L, Van den Berghe S, Roets E, van Wessel S, Hamerlynck T.

Operative hysteroscopy in the minimally invasive management of interstitial
pregnancy and interstitially retained products of conception : a case report and
systematic literature review. Eur J Obstet Gynecol Reprod Biol. 2021;265:54–9.
Hamel CC, van Wessel S, Carnegy A, Coppus SFPJ, Snijders MPML, Clark J, et al.
Diagnostic criteria for retained products of conception : a scoping review. Acta
Obstet Gynecol Scand. 2021;100(12):2135–43.
| 165
van Wessel S, Hamerlynck T, Schoot BC, Weyers S. Hysteroscopy in the Netherlands
and Flanders: a survey amongst practicing gynaecologists. Eur J Obstet Gynecol
Reprod Biol. 2018;223:85–92.
Bosteels J, van Wessel S, Weyers S, Broekmans F, D’Hooghe T, Bongers M, et al.

Hysteroscopy for treating subfertility associated with suspected major uterine cavity
abnormalities. Cochrane Database Syst Rev. 2018;(12).
van Wessel S, Dehaene I, Van Nieuwenhove Y, Coppens M, Scharpe K, Roelens K.

Unusual bariatric complication in pregnancy. Gynecol Obstet Case Rep. 2016;2(1).
van Wessel S, Van Kerrebroeck H, VAN BOGAERT V, Tummers P, Van den Broecke R.
Primary intestinal type adenocarcinoma of the female genital tract, arisen from a
tubulo-villous adenoma: case report. Gynecol Oncol Case Rep. 2013;4:63–5.
166 |
ADDENDA
ADDENDUM 1 Milestones in hysteroscopic development
1804 The Light conductor ‘Lichtleiter’: the visualisation of body cavities (Philipp
Bozzini)
1853 Cystoscope ‘l’endscope’: diagnosis and treatment of the bladder (Antonin
Jean Désormeaux)
1865 Modified Désormeaux’s endoscope: petroleum and camphor (Francis Cruise)
1869 Hysteroscopy (Désormeaux’s endoscope): diagnosis and treatment of an
endometrial polyp (Diomede Pantaleoni)
1879 Modified Désormeaux’s endoscope: distal illumination (Maximilian Nitze)
1907 Contact hysteroscope (Charles David)
1914 Continuous-flow hysteroscope ‘Uteroscope’ using heated saline (Alfred
Heineberg)
1925 CO2 for uterine distension (Isidor Rubin)
1927 Operative hysteroscope ‘Kurettoscope’: biopsy, removal of abnormal tissue
and corneal electrocoagulation as method of sterilization (Felix von Miku
licz-Radecki & A. Freund)
1934 Measuring intrauterine pressure using saline (Charles Schroeder)
1934 Calibrate in and outflow to achieve adequate uterine distension and
minimize intraperitoneal spill (R. Segond)
1952 Cold light (Max Fourestier, Jacques Vulmière & Amedee Gladu)
1957 Balloon distension of the uterine cavity (William Norment)
1959 Rod-lens endoscope (Harold Horace Hopkins)
1966 Flexible hysteroscope (Oscar Aguero)
1967 Ambulatory approach using a pediatric cystoscope (Fritz Menken)
1970 35% Dextran for uterine distension (Karin Edström & Ingmar Fernström)
5% dextrose in water for uterine distension using pressure cuff (Rodolfo
Quinones-Guerrere)
1971 Reintroduction of CO2 for uterine distension (Hans-Joachim Lindemann)
Luviskal-K 90 for uterine distension (Fritz Menken)
1975 Saline for uterine distension (Osamu Sugimoto)
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1976 Hysteroscopic removal of a submucous fibroid (urologic monopolar
resectoscope) (Robert Neuwirth)
1980 Type 1 Hamou Microcolpohysteroscope (Jacques Hamou) Video camera
1983 Endometrial ablation (urologic monopolar resectoscope) (Alan
DeCherney)
1987 Resectoscope designed for gynecological use (Jean Paul Hallez)
1989 FDA approval of the resectoscope for gynecological procedures
1995 ‘cold loop’ for mechanical enucleation of submucosal fibroids with an
intramural component (Ivan Mazzon)
1996 Office operative hysteroscopy (Stefano Bettocchi)
1997 Vaginoscopy (Stefano Bettocchi & Luigi Selvaggi)
Hysteroscopic resection of retained products of conception (Mordechai
Goldenberg)
1997 5fr bipolar instruments: Versapoint^TM I Bipolar Electrosurgical System
(Ethicon, USA)
Second-generation devices for endometrial ablation
1998 Automated delivery systems to limit the risk of fluid intravasation
2005 Mechanical hysteroscopic tissue removal sevice: Truclear™ 8.0 (Smith &
Nephew, UK) (Mark Hans Emanuel) Resectoscope with automatic chip
aspiration: Resection Master (Richard Wolf, Germany) (Adolf Gallinat)
2010 Miniature resectoscope: 16 Fr Gubbini miniresectoscope
(Tontarra, Germany) (Giampietro Gubbini)
2012 Mini mechanical hysteroscopic tissue removal sevice: Truclear™ 5C (Smith &
Nephew, United Kingdom)
2016 Manually driven hysteroscopic tissue removal device: Resectr™ 5 and 9 Fr.
(MinervaSurgical, USA)
2018 Reusable hysteroscopic tissue removal device: Intrauterine Bigatti Shaver
(IBS®) (Storz, Germany)
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ADDENDUM 2 Overview of the mechanical hysteroscopic tissue removal
systems
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DANKWOORD
Het laatste onderdeel van ‘het boekje’, niet in het minst onbelangrijk, een
woord van dank. Het was een avontuur waarin overleggen, doorzetten,
geduld hebben, en soms er gewoon het beste van maken, werden
afgewisseld door enthousiasme, amusement, leuke uitstapjes en aangename
samenwerkingen.
De eerste woorden van dank gaan uit naar de promotoren om steeds

beschikbaar te zijn om mij met raad en daad bij te staan.
Prof. Dr. Steven Weyers, bedankt voor het vertrouwen en de
mogelijkheden op wetenschappelijk en op klinisch vlak. Hierdoor ben ik
kunnen groeien tot de gynaecologe die ik vandaag ben. Bedankt om in dit
avontuur het pad recht te trekken als het hobbelig dreigde te worden.
Prof. Dr. Dick Schoot, bedankt voor je enthousiast ‘out of the box’-denken
dat aanleiding geeft tot tal van onderzoekideeën. Bedankt om je ‘Resectr’
project aan mij toe te vertrouwen. Het hysteroscopiespreekuur in Catharina
was best gezellig, helaas bracht Corona een einde aan de bezoekjes.
Prof. Dr. Jan Bosteels, Napoleon heeft geen geheimen meer voor jou, maar
dat geldt ook voor het ‘Cochrane review’ proces en het opzetten van RCTs.
Bedankt om jouw ervaringen te delen. Bedankt om mij te introduceren in
de ‘AGNOHSTIC’ wereld en om duidelijkheid te brengen bij dilemma’s en
vraagstukken. We zetten dit avontuur nog even verder.
Prof. Dr. Tjalina Hamerlynck, Tjalina, woorden van dank schieten tekort.
Bedankt om begeleider te willen zijn van dit avontuur. Ik ontmoette jou
tijdens mijn stagejaar gynaecologie in de opleiding geneeskunde.
Je enthousiasme, gedrevenheid en liefde voor de minimaal invasieve
gynaecologie sprongen over. Je nam me mee op sleeptouw wat resulteerde
in dit boekje, maar ook in de klinische activiteiten die ik vandaag met veel
enthousiasme en plezier doe. Bedankt om de rots in de branding te zijn,
de puntjes op de ‘i’ te zetten, maar ook om de dingen in perspectief te
plaatsen en te relativeren. We zetten deze warme samenwerking verder.
Een zeer grote erkentelijkheid gaat uit naar de studiecoördinatoren en het

studieteam van het UZ Gent. De ondersteuning die ik van jullie kreeg is
onbeschrijfelijk, jullie zijn stuk voor stuk goud waard.
Sara en Eline, jullie zijn de constanten in dit avontuur. Karolien, Rebecca,
Ellen en Sofie, jullie reisden een stukje mee. Judith jij werd op het einde
helemaal ondergedompeld. Bedankt allen om er over te waken dat alles
correct verliep, om de administratie min of meer verstaanbaar te maken,
om alles in goede banen te leiden en om mij op tijd terug te fluiten als ik al
begon te vliegen. Een bijzondere dankjewel aan het GYNOBS en ARG
studieteam. Dankzij jullie inzet en overzicht ontsnapt er geen patiënt en
geen worksheet aan de aandacht.
Dank aan alle mede-auteurs voor de kritische en aangename samenwerking
om elk artikel tot een goed einde te brengen. Bedankt Mark Hans
| 171
Emanuel, om het idee voor de ‘NIPHY’ studie te lanceren, en om te zetelen
in de examencommissie. Bedankt Astrid Vanhulle, om de ‘NIPHY’ studie mee
tot leven te brengen in het kader van je masterproef. Bedankt Julie
Rombaut, om de ‘NIPHY’ studie in leven te houden tijdens mijn
zwangerschapsafwezigheid (en niet alleen de studie). Bedankt Huib van
Vliet, als lid van de ‘morcellator studies’, om je kritisch nazicht en je
positivisme. Ik wist dit telkens erg op prijs te stellen. Bedankt Nele
Coryn, voor onze ontelbare belrondes naar patiënten. Fijn dat jij nu ook een
bureaugenootje geworden bent. Bedankt aan alle hoofdonderzoekers van de
AGNOHSTIC studie, Prof. Dr. Christine Wyns, Prof. Dr. Michelle Nisolle,
Dr. Valerie Schutyser, Prof. Dr. Carla Tomassetti, Prof. Dr. Jasper Verguts en
Dr. Bart De Vree, voor jullie werkijver voor deze ‘intensieve’ studie.
Het protocol hebben we alvast gepubliceerd. Het einde van de studie is in
zicht, we bijten nog even door met includeren en ronden het verhaal mooi
af. Ook een woord van dank voor de studiecoördinatoren en de
studieteams van alle centra die betrokken zijn bij de studies. Bedankt
Manita Coolen voor het speurwerk om op al mijn vragen een antwoord te
kunnen geven. Bedankt Laurence Beausaert, Marie Timmermans, Elsie
Nulens, Laurien De Greef, Tine Op de Beeck, Ina Callebaut en Régine
Bauters, want de AGNOHSTIC studie neemt veel van jullie tijd in beslag,
jullie inzet wordt enorm geapprecieerd.
Een oneindige dankjewel aan iedereen die, op welke manier dan ook,
betrokken was bij het includeren van patiënten: assistenten, ARG collega’s,
verloskunde collega’s, gynaecologie collega’s, verwijzende gynaecologen, …
Mijn verontschuldigingen voor het stalken zijn hier nu misschien wel op z’n
plaats. Hoewel, voor AGNOHSTIC gaan we toch nog even verder.
Nog een speciaal woordje van dank. Bedankt Menekse Göker, om een
bureaugenootje te zijn, voor de vlotte en aangename samenwerking, om
doctoraatvreugde en leed te delen, om te ventileren en te relativeren.
Bedankt Isabelle Dehaene, jouw werkspirit en jouw efficiëntie waarin je
kliniek en wetenschap met elkaar verweeft brachten mij helemaal ‘into
UZ’. Bedankt Chloë Deroo, Glenn Vergauwen en Noortje van Oostrum voor
de ‘hoe deden jullie dat’ vragen. Bedankt Frauke Vanden Meerschaut voor
de ‘hoe zat het nu alweer’ fertiliteitsvragen. Hopelijk werd je er niet
horendol van (en het is nog niet gedaan). Bedankt Philippe Tummers om mij
aan te zetten tot het schrijven van dit geheel. Bedankt Celine Blank om me
wegwijs te maken in de MEC-U wereld. Bedankt Lien Dhaenens om het PhD-
schuitje te delen. Bedankt Griet Vandenberghe om je af te vragen waarom
een zwangere na 24 weken nog ’s nachts in het UZ ronddoolt.
Dank aan de leden van de examencommissie voor jullie engagement, tijd

en inzet om dit doctoraat te beoordelen.
Dank aan alle deelnemers, zonder jullie was er geen sprake van dit
avontuur.
172 |
Een trouwe supporter aan de zijlijn, een welgemeende dankjewel Evelyn
Maes om te zijn wie je bent, onvoorwaardelijk en altijd daar. Deze periode
is voor jou minstens even spannend zoniet spannender. Ik duim voor jou.
Bedankt mama en papa om jullie telkens weer in 1000 bochten te wringen,

om de brandjes te blussen en de deuren voor mij open te zetten. Alice en
Julia kunnen altijd op jullie rekenen, dankjewel.
Bedankt Joni, om een broer uit de duizend te zijn en om alles te voorzien

van de nodige humor en luchtigheid.
Het allerlaatste dankwoord is voor Bart, Alice en Julia. Bart, ook voor jou
schieten woorden van dank te kort. Dat ik hier vandaag kan staan is mede,
en vooral, dankzij jou. Een onbeperkte steun met oneindig veel geduld,
maar de tijd om af te ronden is toch welgekomen.
‘Ik ben er binnen 5 minuten’ wint hopelijk vanaf nu aan geloofwaardigheid.
Alice en Julia, nu komt er extra tijd om te genieten van onze momenten
samen.
| 173

Van Wessel Steffi - Optimizing Hysteroscopic Treatment

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OPTIMIZING

Steffi van Wessel

Steffi van Wessel

© Steffi van Wessel, 2023

Steffi van Wessel

Academic year: 2022 - 2023

Prof. Dr. Benedictus Schoot

Prof. Dr. Jan Bosteels

Prof. Dr. Wouter Froyman

Dr. An-Sofie Goessaert

Prof. Dr. Mark Hans Emanuel

Prof. Dr. Björn Heindryckx

Dr. Frauke Vanden Meerschaut

Dr. Noortje van Oostrum

Part I Pain relief in office diagnostic hysteroscopy

Part II Instrumentation for operative hysteroscopy

Part III Reproductive outcome after operative hysteroscopy

Chapter 8............................................................................. 113

Chapter 9............................................................................. 131

About the author..................................................................... 163

D&C Dilation and Curettage

ESGE European Society for Gynaecological Endoscopy

ESHRE European Society of Human Reproduction and Embryology

Fr French (= diameter in millimeters x 3)

FIGO International Federation of Gynecology and Obstetrics

IDEAL Idea, Development, Exploration, Assessment, Long-term study

ISGE International Society for Gynecologic Endoscopy

IUA IntraUterine Adhesions

IUD Intrauterine Device

MAUDE Manufacturer and User Facility Device Experience

NaCl Sodium Chloride

NSAIDs Non-Steroid Anti-Inflammatory Drugs

PBAC Pictorial Blood Assessment Chart

RCT Randomized Controlled Trial

RPOC Retained Products Of Conception

SIS Saline Infusion Sonography

STEPW Size, Topography, Extension, Penetration, lateral Wall position

TENS Transcutaneous Electrical Nerve Stimulation

VAS Visual Analogue Scale

Hysteroscopy is a minimally invasive method in which a hysteroscope is used

During a diagnostic hysteroscopy, evaluation takes place of the

An operative hysteroscopy allows to treat intrauterine pathology (Figure 1),

Figure 1 Intrauterine pathology

The historical milestones in the development of hysteroscopy are shown in

Innovations in hysteroscopic procedures only started in the mid 90’s, with

Modern hysteroscopy anno 2023 consists of a video camera and monitor, a

In 1989 the resectoscope became available. This device consists of a

© KARL STORZ SE & Co. KG, Germany (used with permission)

The latter is associated with a risk of serious complications such as fluid

© KARL STORZ SE & Co. KG, Germany (used with permission)

In 1997, 5 Fr bipolar instruments were developed, featuring two disposable

Figure 4 5 Fr bipolar instruments

A. Twizzle Tip electrode B. Spring Tip electrode

In 2005, the mechanical hysteroscopic tissue removal system became

Figure 5 Mechanical hysteroscopic tissue removal system

The latest innovation in the field of hysteroscopic tissue removal systems is

Figure 6 Manual hysteroscopic tissue removal device

Resectr™ (MinervaSurgical) (used with permission)

HYSTEROSCOPIC TREATMENT OF INTRAUTERINE PATHOLOGY