Journal Pre-proof

Hysteroscopic Morcellation Versus Curettage for Removal of Retained Products of

Conception: A multicenter randomized controlled trial

Liselot P. WAGENAAR, Tjalina W. HAMERLYNCK, MD, PhD, Celine M. RADDER,

MD, PhD, Louisette W. PETERS, Steven WEYERS, MD, PhD, Benedictus C.
SCHOOT, MD PhD, Huib A. van VLIET, MD, PhD
PII: S0015-0282(23)01722-3
DOI: https://doi.org/10.1016/j.fertnstert.2023.08.956
Reference: FNS 34466

To appear in: Fertility and Sterility

Received Date: 23 March 2023

Revised Date: 19 August 2023
Accepted Date: 23 August 2023

Please cite this article as: WAGENAAR LP, HAMERLYNCK TW, RADDER CM, PETERS LW, WEYERS
S, SCHOOT BC, van VLIET HA, Hysteroscopic Morcellation Versus Curettage for Removal of Retained
Products of Conception: A multicenter randomized controlled trial, Fertility and Sterility (2023), doi:
https://doi.org/10.1016/j.fertnstert.2023.08.956.

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Copyright ©2023 Published by Elsevier Inc. on behalf of the American Society for Reproductive
Medicine
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1 Hysteroscopic morcellation of RPOC: RCT

2 Hysteroscopic Morcellation Versus Curettage for Removal of

3 Retained Products of Conception: A multicenter randomized

4 controlled trial

5 Liselot P. WAGENAAR1*, Tjalina W. HAMERLYNCK2,3 MD, PhD, Celine M. RADDER, MD, PhD4, Louisette

6 W. PETERS4, Steven WEYERS2,3 MD, PhD, Benedictus C. SCHOOT1,2 MD PhD, and Huib A. van VLIET1,2

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7 MD, PhD

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8

9
1.
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Department of Obstetrics and Gynecology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The

Netherlands;
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2.
10 Department of Human Structure and Repair, Ghent University, Ghent, Belgium;
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3.
11 Women’s Clinic, Ghent University Hospital, Ghent, Belgium;
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12 Department of Obstetrics and Gynecology, OLVG, Amsterdam, The Netherlands;
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*
13 Corresponding author;
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14 Liselot Wagenaar, MD
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15 Department of Obstetrics and Gynecology, Catharina Hospital

16 Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands

17 Tel: +31 6 15459955

18 E-mail: Liselot.wagenaar@catharinaziekenhuis.nl

19 Article type: Clinical Trial

20 Funding: H.v.V received an unrestricted grant from the External Research Program from Medtronic.

21 The Ghent University Hospital Research Center receives unrestricted external research support from

22 Medtronic for the ongoing RIGHT trial

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23 Disclosure Statement: H.v.V. and B.S. received fees from Medtronic on an hourly basis for lectures on

24 hysteroscopic morcellation. All the fees were donated to a foundation which promotes research in

25 obstetrics and gynecology.

26 Ghent University Hospital received a fee from Medtronic for a lecture on RPOC by T.H.

27 Attestation statement:

28 • The subjects in this trial have not concomitantly been involved in other randomized trials (If

29 applicable).

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30 • Data regarding any of the subjects in the study has not been previously published unless

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31 specified.

32 • -p
Data will be made available to the editors of the journal for review or query upon request.
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33 Data sharing statement: The anonymized data will be available and reusable for other researchers
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34 upon reasonable request according to GCP and FAIR principles.

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35 345 words for abstract and 3574 words for text

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36 This work was presented as an oral presentation at the European Society for Gynecological
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37 Endoscopy’s 31st Annual Congress, Lisbon, Portugal, October 2-5, 2022.

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38
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39 Capsule

40 Hysteroscopic morcellation leads to more one-step complete removal of retained products of

41 conception compared with ultrasound guided curettage.

42 Abbreviations

43 D&C Dilatation and Curettage

44 EVA Electric vacuum aspiration

45 HM Hysteroscopic morcellation

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46 HR Hysteroscopic removal

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47 MPR Manual placenta removal -p
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48 IUA Intrauterine adhesion
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49 RPOC Retained products of conception

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50 SIS Saline infusion sonography

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51 TOP Termination of pregnancy

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52
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53 Abstract

54 Objective: To study the comparison between hysteroscopic morcellation of retained products of

55 conception with ultrasound guided electric vacuum aspiration in terms of intrauterine adhesion

56 formation, as well as efficacy and complications.

57 Design: Randomized controlled, non-blinded trial conducted in three teaching hospitals and one

58 university hospital from April 2015 to June 2022.

59 Subjects: One-hundred seventy-three women with retained products of conception on ultrasound,

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60 ranging from 1 to 4 cm, were randomized to receive either hysteroscopic morcellation or electric

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61 vacuum aspiration.

62
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Intervention: Hysteroscopic morcellation was performed with the TruClear™ System (Medtronic,
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63 Minneapolis, MN, USA). Electric vacuum aspiration was performed using an 8 or 10 mm flexible
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64 plastic Karman cannula under ultrasound guidance. Women allocated to vacuum aspiration
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65 underwent the procedure as soon as possible.

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66 Main Outcome Measures: In the hysteroscopic morcellation group, an office diagnostic hysteroscopy
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67 was planned a minimum of 6 weeks after the end of pregnancy, followed by retained product of

68 conception removal at least 8 weeks after the end of the pregnancy. Postoperatively, an office

69 second-look hysteroscopy was scheduled to assess the primary outcome of intrauterine adhesions.

70 Results: Postoperative intrauterine adhesions were seen in 9 of 63 patients (14.3%) in the

71 hysteroscopic morcellation group and 13 of 64 patients (20.6%) in the vacuum aspiration group (-6%

72 [-19.1% to 7.1%], p=.348). Significantly more retained product of conception were completely

73 removed by hysteroscopic morcellation compared to vacuum aspiration (95.2% vs 82.5% (-14%[-

74 24.9% to -3.1%]), and additional operative hysteroscopy was less frequently necessary in the

75 hysteroscopic morcellation group (12.5%) compared to the vacuum aspiration group (31.3%) (-20.1%

76 [-34.3% to -6%]). Median operating time was shorter for vacuum aspiration compared with
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77 hysteroscopic morcellation (5.80 min vs 7.15 min) No differences were observed between

78 hysteroscopic morcellation and vacuum aspiration for the occurrence of intra- or postoperative

79 complications (5.5% vs 5.0%, and 2.7% vs 1.3%, respectively).

80 Conclusion: In our randomized controlled trial, no significant differences were found in the

81 occurrence of intrauterine adhesions and complications. However, the retained products of

82 conception were more often completely removed by hysteroscopic morcellation than vacuum

83 aspiration, and the hysteroscopic morcellation group required fewer additional hysteroscopic

84 treatments.

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85 Trial registration: NTR4923 (https://trialsearch.who.int/Trial2.aspx?TrialID=NTR4923). Date of

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87
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registration: 23-11-2014, date of initial participant enrollment: 01-01-2015

Keywords
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88 Dilation and curettage; electric vacuum aspiration; hysteroscopic morcellation; intrauterine
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89 adhesions; retained products of conception

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90
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91 Introduction

92 Retained products of conception (RPOC) occur after up to 1 in 17 pregnancies(1). When expectant or

93 medical treatment fails in symptomatic patients, surgical removal is indicated.

94 Dilation and curettage (D&C) is the mostly performed procedure for removing RPOC, using a

95 metal curette or, vacuum aspiration(2-4). Ultrasound guidance may enhance safety and

96 completeness of removal(5-8). Nevertheless, the risks of curettage are hemorrhage, uterine

97 perforation, infection, and formation of intrauterine adhesions (IUAs) leading to subsequent

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98 infertility(1). IUAs have been reported in as many as 38% of patients after curettage for

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99 miscarriage(1-4, 9, 10). The risk of IUAs after repeated procedures rises to 40%(9, 11, 12). Recently,

100 -p
hysteroscopic RPOC removal was found to provide a good alternative for curettage(9, 13-17).
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101 Hysteroscopic removal (HR) allows selective treatment of RPOC under “visual control” with
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102 minimal effect on the adjacent endometrium. This may lead to more complete removal and reduced
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103 trauma, thereby decreasing the risk of inflammation, scarring, and IUA formation(9, 16, 17). In 1997,
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104 Goldenberg et al. described the first case series on HR of RPOC, and since then, several observational
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105 studies have been published(1, 17-20). A systematic review combining these studies observed that
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106 HR might be preferable to curettage because of fewer IUAs (13% vs 30%) and more complete

107 evacuations (1% vs 29%)(9). However, no RCTs have been published so far, and most published

108 studies are retrospective, without a control group. There are two methods of HR of RPOC: the ‘cold

109 loop’ technique, using the resectoscope’s loop as a curette without electricity, and hysteroscopic

110 morcellation (HM), using a mechanical morcellation device(21-24). An RCT comparing these two

111 techniques for RPOC removal showed comparable rates of complete removal, tissue availability, and

112 IUAs formation, except for a shorter operating time with HM (24).

113 At the time our study was initiated, no RCTs had been conducted comparing hysteroscopy

114 with curettage for RPOC removal. Our study aimed to determine the risk of IUA formation, as well as

115 the efficacy and safety of HM compared with ultrasound guided electric vacuum aspiration (EVA).
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116

117 Materials and Methods

118 This multicenter, randomized controlled, investigator-initiated, open-label trial was performed in

119 three teaching hospitals: the Catharina Hospital (Eindhoven, the Netherlands), OLVG location East

120 (Amsterdam, the Netherlands), OLVG location West (Amsterdam, the Netherlands), and one

121 university hospital, the Ghent University Hospital (Ghent, Belgium) between April 2015 and June

122 2022. The study was approved by the Regional Medical Ethical Committee (MEC-U) and local

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123 institutional ethical committees, and by the Ethical Committee of the Ghent University Hospital,

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124 Belgium. The study was registered in the Dutch Trial Register (NTR4923). All patients gave written

125 informed consent. -p

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126 Design
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127 Adult women with an ultrasonographic image suggestive for RPOC ranging from 1 to 4 cm in
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128 diameter, after miscarriage, termination of pregnancy (TOP) or delivery, were eligible to participate.
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129 Sonographic features considered indicative of RPOC included: the presence of thickened endometrial
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130 echo complex (≥10 mm) or an intrauterine mass with or without translesional vascularity(25).
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131 Women who met the inclusion criteria were first invited to participate in this RCT. If they did not

132 want to participate in the RCT due to a preference for a specific treatment option after counseling,

133 they were asked to take part in the observational arm of the study. This observational cohort runs

134 concurrently with the RCT, serves as external validity, and will add value to this RCT(26-31). Patients

135 presenting with fever, with evidence of malignancy, or a contra-indication for surgery were excluded.

136 Complications and symptoms were recorded. Patients were randomized to receive either HM or EVA

137 if RPOC was diagnosed and surgical intervention was indicated. The end of pregnancy was in all cases

138 defined as the moment of expulsion or removal of the pregnancy. Women allocated to EVA

139 underwent the procedure as soon as possible after the diagnosis of RPOC. In the HM group, the

140 therapeutic hysteroscopy was performed at least eight weeks after the end of pregnancy. A
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141 hysteroscopy to confirm the RPOC took place before the therapeutic hysteroscopy according to

142 hospital protocol (Catharina hospital and Ghent University Hospital) because of logistical reasons.

143 The minimal interval of at least 8 weeks was chosen to prevent adverse events such as rapid fluid loss

144 and incomplete RPOC removal that have been described in relation to early hysteroscopic

145 treatment(1, 24). The procedures were carried out by either staff members or residents in training

146 under direct supervision, and patients received either conscious sedation, general or spinal

147 anesthesia in an outpatient setting.

148 Interventions

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149 The technique of HM has been described previously(21, 22, 24). HM was performed with the

150

151
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TruClear™ 8.0 System or Elite Hysteroscope Plus, using the TruClear™ Soft Tissue Shaver Plus

(previously: Smith & Nephew, Andover, MA, USA; currently: Medtronic, Minneapolis, MN, USA). The
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152 hysteroscope was inserted under direct visualization after dilating the cervix up to Hegar 9-10. Saline
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153 was used for uterine distention and irrigation. Fluid balance was monitored using the HysteroLux™
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154 (previously: Hysteroscopic Fluid Management System Smith & Nephew, Andover, MA, USA;
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155 currently: Medtronic, Minneapolis, MN, USA) with a maximum pressure setting of 120 mmHg and a

156 maximum flow of 700 mL/min.

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157 Dilatation and curettage, i.e., EVA, was performed using an 8 or 10 mm flexible, plastic

158 Karman cannula with two lateral openings. A vacuum source with a maximum suction power of 0.8

159 bar was used to aspirate the tissue. The cervix was dilated with Hegar dilators up to 8-10, followed

160 by insertion of the cannula under transabdominal ultrasound guidance. Ultrasound of the uterus was

161 carried out during the whole procedure. The cannula was gently rotated in both directions, removed

162 when needed, and reinserted in the same manner.

163 Rein et al. observed IUA in 28% of the patients after ultrasound-guided curettage using a

164 metal curette, and Hamerlynck et al. found an IUA percentage of 4% after HM(17, 22). For the

165 sample size calculation, we used a difference of 16% in the occurrence of IUA between the two
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166 methods. With the assumption that the number of IUA after vacuum curettage is lower than after

167 curettage with a metal curette, we assumed 20% of IUA in the curettage group. Considering an alpha

168 of 0.05 and a power of 80%, a total required sample size of 126 was calculated. Randomization was

169 performed using a random sequence generator (random.org) without blocking. The allocation

170 sequence was concealed using sequentially numbered sealed opaque envelopes stratified by center.

171 The envelopes were kept by a person not involved in the study, who opened the envelope after the

172 participant’s inclusion and passed on the treatment to the investigator.

173 Outcome measures

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174 The primary outcome was the presence of IUAs diagnosed by second-look hysteroscopy in an

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176
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outpatient setting after at least one menstruation or a minimum of 8 weeks after RPOC removal. The

patients received no anesthesia or sedation. Intrauterine adhesions were classified as mild,

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177 moderate, or severe according to the Valle and Sciarra classification(32). Mild adhesions were
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178 defined as filmy adhesions, moderate adhesions as fibromuscular and severe adhesions were
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179 composed of connective tissue lacking any endometrial lining. Either type of adhesions could lead to
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180 partial or total occlusion of the cavity.

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181 Secondary outcomes included installation time (defined as the time to set up the

182 hysteroscope or EVA cannula ready for use, including cervical dilation), operating time (defined as

183 the time from cannula or hysteroscope introduction until removal of the instrument at the end of the

184 procedure) and procedure time (defined as the sum of installation and operation time), conversion

185 rates, intra- and postoperative complications (including: fluid deficit >2500 mL or fluid related clinical

186 consequences, hemorrhage (>500 mL), uterine perforation, burns, and infection), pathology results,

187 the completeness of removal at second-look hysteroscopy, and the need for additional treatment.

188 Complications were graded according to the modified Clavien-Dindo classification. Grade 1 is defined

189 as any deviation from the normal postoperative course without the need for pharmacological

190 treatment or surgical, endoscopic, and radiological interventions. Allowed therapeutic regimens are
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191 drugs as antiemetics, antipyretics, analgetic, diuretics and electrolytes and physiotherapy. Grade 2 is

192 defined as requiring pharmacological treatment with drugs other than such allowed for grade 1

193 complications; blood transfusions and total parenteral nutrition are also included. Grade 3 is defined

194 as requiring surgical, endoscopic or radiological intervention. Grade 4 is defined as a life-threatening

195 complication, and grade 5 is defined as death of patient(33).

196 Statistical analysis

197 Data were collected using REDCap (Research Electronic Data Capture) and analyzed using

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198 SPSS (IBM SPSS Statistics 25.0, IBM Corp., Armonk, NY, USA). Normality was checked by looking at

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199 the histograms, skewness and kurtosis, and was formally tested with the Kolmogorov-Smirnov test.

200

201
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For normally distributed continuous variables, means and standard deviations are calculated. For

non-normally distributed continuous variables, median and inter-quartile ranges are reported.
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202 Categorical outcomes are presented as frequency and percentage per study group and analyzed
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203 using the Chi-square Test or the Fisher’s Exact Test are appropriate. All point estimates for the
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204 differences between groups are presented with their 95% CIs. Skewed time variables were log-
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205 transformed and analyzed with the Student t-test to compare arithmetic means. Both an intention-

206 to-treat and a per-protocol analysis was performed. The level of significance was set at p ≤0.05.
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207 Results

208 One hundred and seventy-three women were included, 70 women in the Catharina hospital, 61

209 women in the OLVG East hospital, 5 women in the OLVG West hospital, and 37 women in the Ghent

210 University Hospital. 87 women and 86 women were randomly allocated to the HM and the EVA

211 group (Supplemental Fig. 1) respectively.

212 Baseline characteristics did not differ between the two groups (Supplemental Table 1). No

213 differences in the history of cesarean section, manual placenta removal (MPR), curettage,
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214 hysteroscopic RPOC removal or previously diagnosed IUAs or congenital malformations were found

215 between the two groups.

216 Data on the pregnancies immediately preceding the RPOC diagnosis are outlined in Table 1.

217 No differences were found between the two groups regarding the trimester the pregnancy ended,

218 expulsion or mode of delivery, just as there was no difference in the proportion of women who

219 underwent MPR or curettage or both. The median interval between the end of pregnancy and the

220 RPOC removal was different between the two groups with a median of 10 weeks (8-12 weeks) in the

221 HM group versus 8 weeks (7-10 weeks) in the EVA group.

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222 Table 1, summarizes the clinical presentation, and the characteristics of the RPOC. Most

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224
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women presented with abnormal uterine bleeding (AUB), with or without abdominal pain. In 90.8%

of the patients in the HM group, office hysteroscopy was performed in the diagnostic workup. The
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225 office hysteroscopy occurred earlier than six weeks in 4 patients. In the EVA group, the presence of
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226 RPOC was mainly assessed sonographically (91.8%). No differences were observed in the RPOC
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227 diameter between the groups with a median of 20 mm (15-25 in the HM group, 15-28 in the EVA
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228 group).
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229 Table 2 presents surgery data. Twenty patients did not undergo HM or EVA due to

230 spontaneous expulsion (10 in the HM group, 5 in the EVA group) or due to outpatient removal (3

231 patients underwent hysteroscopic removal with 5Fr forceps in the HM group, and one patient

232 underwent RPOC removal cervically in the EVA group). The installation time and operating time

233 varied between the two groups. Consequently, the procedure time was statistically significantly

234 reduced in the EVA group. The number of hysteroscope insertions was lower compared with the

235 number of insertions of the curettage cannula. Conversion to curettage occurred in 4 patients the

236 HM group (reasons: bad visibility (n=1), poor distension/rapid fluid loss (n=2), and remnant too large

237 to remove completely by hysteroscope (n=1)). Conversion from EVA to HM took place in 1 patient

238 because the RPOC was found to be too adhesive. In the HM group, four intraoperative complications
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239 occurred (Table 2). Three out of 73 women had a grade 1 intraoperative complication: 1 perforation

240 during dilation, with complete RPOC removal still possible; 1 hemorrhage where conversion to

241 curettage was necessary; and 1 fluid deficit of 2500 mL without clinical consequences. One woman

242 had a perforation during dilation, leading to procedure discontinuation and thus incomplete RPOC

243 removal (grade 2 complication). Two women in the HM group had a postoperative hemorrhage. One

244 woman was hospitalized for one day for observation and medical treatment, two days after the

245 initial procedure (grade 2 complication). The other woman was re-hospitalized three times for

246 persistent hemorrhage, which required medical management and two emergency curettages with

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247 eventual conversion to operative hysteroscopy for suspected residual RPOC. Postoperative

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248 observation in the intensive care unit was required (grade 4 complication). In the EVA group, four

249
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intraoperative complications were observed. Three patients had a grade 1 intraoperative
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250 complication: 1 hemorrhage, and 2 perforations, with complete RPOC removal. One women in the
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251 EVA group had a grade 2 complication, namely perforation during surgery, which resulted in an
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252 incomplete procedure. In the EVA group, one woman had a postoperative complication consisting of
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253 a perforation for which a laparoscopic repair was performed (grade 3b).
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254 A second look hysteroscopy was performed in 63 out of 73 patients (86.3%) in the HM group
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255 and 64 out of 80 (80%) in the EVA group (Table 4) The hysteroscopy took place after a median of six

256 weeks (IQR 6-9 weeks) in the HM group, compared with a median of 7.5 weeks (IQR 6-9 weeks) in the

257 EVA group. There were no statically significant differences in IUAs between the two groups (-6% [-

258 19.1% to 7.1%], p=.348)(Table 3) In the HM group, IUAs occurred in 14.3% of patients (9/63), of

259 which four were graded as mild, three as moderate, and two as severe. Five patients in the HM group

260 had pre-existing IUAs (mild n=2, moderate n=2, not graded n=1). In these patients, four women had

261 no IUAs at the second look hysteroscopy, and one had mild adhesions. Hence, de novo adhesions

262 were found in 12.7% of patients in the HM group. 20.6% of EVA patients had adhesions, of which

263 three were graded as mild, six as moderate, and four as severe. Of the six EVA patients in whom a

264 hysteroscopy was performed pre-operatively, none had pre-existing IUAs.

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265 Complete RPOC removal was observed in 60/63 (95.2%) cases in the HM group and 52/64

266 (82.5%) cases of the EVA group (-14% [-24.9% to -3.1%])(Table 4). Fewer additional hysteroscopic

267 treatments were needed in the HM group compared to the EVA group, 8/63 (12.5%) versus 21/64

268 (32.8%) of patients (-20.1% [-34.3% to -6.0%])respectively. In two patients in the HM group,

269 persistent RPOC was removed, five underwent adhesiolysis, and one patient underwent both in the

270 same session. In eight patients of the EVA group, persistent RPOC was removed, 12 patients

271 underwent adhesiolysis, and one patient underwent both in the same session. In the HM group,

272 there was one patient who underwent an additional curettage because of persistent RPOC.

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273 In five of the 153 included patients the intervention was converted to the other technique.

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274 Per-protocol analysis confirmed that the two methods did not differ in IUA formation (p=.178) and

275
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that HM more often completely removed the RPOC (-12.7% [-23.7% to -1.7%]) and additional
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276 hysteroscopic treatment was less often needed in the HM group (-21.9%, [-36% to -7.7%]).
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277 Discussion
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278 Principal findings

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279 In this multicenter randomized controlled trial comparing HM with EVA for RPOC removal we found
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280 no statistically significant difference in IUA formation. However, RPOC were more often completely

281 removed with HM versus EVA, and as a result, fewer patients in the HM group required additional

282 hysteroscopy for removing persistent RPOC compared with the EVA group. No significant differences

283 in complication rate were observed between the two groups.

284 Results

285 We found a non-significant difference in IUAs after RPOC removal by HM (14.3%) compared

286 to EVA (20.6%), which is not in line with the systematic review of Hooker et al.(9). This systematic

287 review showed significantly more IUAs occurring after RPOC treatment by curettage (29.6%)

288 compared to HR (12.8%). However, the studies included in the review were non-randomized and

289 heterogenous regarding the timing of the intervention, type of patients included, and curettage
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290 techniques (digital, metal curette, or not specified, with or without ultrasound guidance).

291 Ultrasound-guided vacuum aspiration may lower the risk of IUA formation(5-8). The percentage of

292 IUAs observed after HM in our study was higher than what was reported in the studies of

293 Hamerlynck et al.(22, 24). A possible explanation could be that the incidence of IUAs in patients with

294 RPOC increases due to previous intrauterine procedures, such as MPR (with or without curettage).

295 In accordance with the literature, we observed that RPOC were more often completely

296 removed in one procedure using HM compared to curettage (95% vs 82%). Hooker et al. similarly

297 reported complete removal in 99% of patients treated with hysteroscopy versus 71% with curettage,

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298 representing a difference of 18%(9). This difference can be explained because HR is performed under

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299 direct vision instead of ultrasonography. During hysteroscopy, one can observe whether the RPOC is

300
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completely evacuated, including more adherent RPOC(9, 13-17). Another explanation might be the
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301 timing of the intervention. The median interval for the HM group was ten weeks compared to a
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302 median of seven weeks for EVA possibly resulting in less adherent and more degenerated RPOC. The
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303 higher number of additional hysteroscopic RPOC treatment for incomplete removal may cause an
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304 increased risk of developing IUAs due to repeated intervention, which favors HM as initial RPOC
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305 treatment(4, 9, 12, 14).

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306 Spontaneous expulsion of the RPOC was observed in 11.5% of patients randomized for HM

307 compared with 5.8% of patients randomized for EVA. To our knowledge, spontaneous expulsion in

308 the waiting period until intervention has not been previously described. This study shows that

309 spontaneous expulsion still occurred after more than 6 weeks after the end of the pregnancy. This

310 justifies a long interval between the end of pregnancy and operative treatment. However, a more

311 extended waiting period does not always have the preference of the patient. Although in the cohort

312 study running along this RCT we observed that most patients opted for hysteroscopic treatment,

313 which entailed a longer interval after pregnancy. Patient preference in relation RPOC removal needs

314 further examination.

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315 The primary outcome of our trial appears to be in line with the recently published RCT of

316 Huchon et al., since we found a low incidence of adhesions after both interventions, and the study by

317 Huchon et al. reports equal pregnancy outcomes between the intervention groups(34). Nevertheless,

318 it is important to address the differences between our study and that of Huchon et al. in terms of the

319 study population and interventions. In our study, we enrolled adult women with ultrasonographic

320 evidence of RPOC measuring 1 to 4 cm in diameter after all types of pregnancy (after miscarriage,

321 termination of pregnancy (TOP) or delivery), and even after initial surgical treatment (manual

322 placental removal and/or curettage). Huchon et al. included individuals who had to undergo surgery

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323 for an incomplete spontaneous abortion, encompassing cases of embryonic death, anembryonic

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324 gestation, as well as RPOC, all with subsequent pregnancy desire. This said, Huchon et al. studied

325
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surgical treatment of early post-miscarriage retentions and RPOC, whereas our trial focused on post-
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326 pregnancy RPOC at a later stage. Vacuum aspiration, albeit not always ultrasound guided in the trial
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327 of Huchon et al., was compared to hysteroscopy in both studies, although we opted for the faster
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328 technique of hysteroscopic morcellation instead of (cold) loop resection. In contrast to the findings of
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329 Huchon et al., who found no benefit of hysteroscopy over vacuum aspiration in women with
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330 incomplete spontaneous abortion of the first trimester, we found that in our study population of
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331 patients with RPOC, hysteroscopic morcellation resulted in a reduced need for re-interventions

332 compared to EVA.

333 In our study, the number of operative complications was low (5.5% and 5.0% for the HM and

334 EVA group, respectively). In the review by Hooker et al., the rates of short-term complications were

335 even lower, being 0% vs 1.4% (0/205 vs 2/142), respectively(9).

336 HM took longer than EVA. Since the difference in operating time was small (7.15min vs

337 5.80min), one might debate whether the difference in total procedure time is clinically relevant.

338 Simplifying the installation steps of the hysteroscopic system would decrease the installation time

339 and, consequently, the procedure time.

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340 Strengths and limitations

341 A strength of this study is that it is the first RCT that investigates the removal of RPOC after

342 all types of pregnancy. In addition, no other studies have described the incidence of spontaneous

343 expulsion between the end of pregnancy and the intervention. Furthermore, we focus specifically on

344 the completeness of removal and describe the additional treatments where necessary. One potential

345 limitation of the study is that we assessed the incidence of adhesions as primary outcome and not

346 the live birth rate. Adhesions are a surrogate outcome for fecundity after operative RPOC removal,

347 with the assumption that adhesions affect live birth rates in later pregnancies. Second, 17% of the

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348 patients (26/153) did not undergo a second-look hysteroscopy, which may have introduced bias into

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349 our data on postoperative IUAs. However, external validation of our results in a cohort study that ran

350
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alongside this study showed the same numbers. Third, our trial was powered for the primary
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351 outcome measure of IUA so formal conclusions cannot be definitively drawn regarding the secondary
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352 outcomes. Fourth, our study was an open-label study.

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353 Conclusions
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354 In conclusion, based on this RCT, no statistically significant difference was observed in the
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355 formation of IUAs or complication rates between HM and EVA for the removal of RPOC. However,
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356 our findings indicate that HM more frequently achieves complete removal of RPOC compared to EVA,

357 resulting in a reduced need for subsequent hysteroscopic treatments for persistent RPOC. Therefore,

358 HM performed under direct visualization may be preferred over ultrasound-guided EVA for achieving

359 one-step complete RPOC removal. Future research should focus on assessing reproductive and

360 obstetric outcomes following both techniques and incorporate a cost-effectiveness analysis.

361

362 Acknowledgment

363 We thank all of our patients for their participation in this study, our colleague gynecologists for the

364 referral of their patients, Connie Rees for her help, and Marcel van ‘t Veer and Saskia Houterman for
 17

365 their guidance on the statistical analysis.

366

367 References

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455
 Supplemental Table 1: Baseline characteristicsa
HM (87) EVA (86)
Age (y) 32 (±4.2) 32 (±4.7)
BMI (kg/m2) 23 [21 – 25] 24 [21 – 26]
Obstetric history
Gravidity 2 (1 – 3) 2 (1 – 3)
Parity 1 (0 – 2) 1 (0 – 2)
Previous cesarean section 10 (11.5) 11 (12.8)
Previous manual placenta removal 3 (3.4) 1 (1.2)
Previous curettage 15 (17.2) 19 (22.1)
Previous operative hysteroscopy 5 (11.1) 4 (8.5)
Previous hysteroscopic RPOC removal 4 (1.1) 2 (2.3)
Previously diagnosed congenital uterine

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malformation 2 (2.3) 2 (2.4)
Previously diagnosed IUAs 0 (0) 0 (0)

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Smoker 5 (5.8) 8 (9.3)
ASA classification 1 (1 – 1) 1 (1 – 1)
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ASA = American Society of Anesthesiologists; BMI = body mass index; EVA = electric vacuum
aspiration; HM = hysteroscopic morcellation; IUAs = intrauterine adhesions; RPOC = retained
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products of conception
a
Data are mean ±standard deviation, median (interquartile range [25% - 75%], or n (%) unless
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otherwise specified. Percentage excludes patients with missing values.

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Table 1: Pregnancy data and clinical presentationa
HM (87) EVA (86)
First trimester 30 (34.5) 37 (43)
Incomplete miscarriage 9 (30) 17 (45.9)
Empty amniotic sac 7 (23.3) 5 (13.1)
Embryo without cardiac activity 13 (43.3) 13 (35.1)
Abortion 1 (3.3) 2 (5.4)
Second trimester 1 (1.1) 3 (3.5)
Abortion 0 (0) 3 (100)
Immature birth 1 (100) 0 (0)
Third trimester 56 (64.4) 46 (53.5)
Premature birth 7 (12.5) 7 (15.2)
Term delivery 49 (87.5) 39 (84.8)

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Expulsion mode first trimester 30 (34.5) 35 (40.7)
Spontaneous 10 (33.3) 13 (37.1)

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Medical treatment 19 (63.3) 18 (51.4)
Electric vacuum aspiration 1 (3.3) 4 (11.4)
Expulsion mode second trimester
-p 1 (1.1) 3 (3.5)
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Spontaneous 1 (100) 0 (0)
Medical treatment 0 (0) 3 (100)
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Delivery mode third trimester 56 (64.4) 46 (53.5)

Spontaneous 40 (71.4) 27 (58.7)
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Induction of labor 4 (7.1) 6 (13.0)

Vacuum extraction 5 (8.9) 2 (4.3)
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Primary cesarean section 3 (5.4) 4 (8.7)

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Secondary cesarean section 4 (7.1) 7 (15.3)

Manual placenta removal 14 (25.0) 7 (14.6)
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Manual placenta removal + curettage 3 (5.4) 0 (0)

Interval end of pregnancy – RPOC intervention 10 [8 – 12] 8 [7 – 10]
(weeks)
Clinical presentation – asymptomatic 19 (21.8) 20 (23.5)
Clinical presentation – symptomatic 68 (78.2) 65 (76.5)
AUB 67 (77) 62 (72.1)
Pain 15 (17.2) 22 (25.6)
Type of imaging
US 5 (5.7) 74 (86)
US and SIS 2 (2.3) 5 (5.8)
US and hysteroscopy 74 (85.1) 5 (5.8)
Hysteroscopy 1 (1.1) 0 (0)
US, SIS and hysteroscopy 4 (4.6) 2 (2.3)
Largest diameter (mm) of RPOC 20 [15 – 25] 20 [ 15 – 28]
Vascularization of RPOC present¥ 10 (25) 20 (40.8)
Vascularization of RPOC absent¥ 30 (75) 29 (59.2)
Location during imaging*
Fundal 29 (33.3) 38 (44.2)
Other° 42 (48.3) 15 (17.4)
Not specified 12 (13.8) 32 (37.2)
Spontaneous expulsion 10 (12) 5 (5.9)
Outpatient removal 3 (3.5) 1 (1.2)
AUB = abnormal uterine bleeding; EVA = electric vacuum aspiration; HM = hysteroscopic
morcellation; SIS = saline infusion sonography; RPOC = retained products of conception; US =
ultrasound
a
Data are mean ±standard deviation, median (interquartile range [25% - 75%], or n (%) unless
otherwise specified. Percentage excluded patients with missing values.
¥ Vascularization is measured during ultrasound as either flow or no flow in or around the RPOC. If
no ultrasound has been performed, the data will be noticed as missing.
* Location as seen during hysteroscopy (golden standard). If no hysteroscopy has been performed,

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the data of the ultrasound or saline infusion sonography were used.
° Location specified as being other than fundal.

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Table 2: Surgery dataa
HM (73) EVA (80) Difference (95% CI)
Installation time (min) 4.42 [3.15 – 5.07] 1.83 [0.73 – 2.87]
Installation timec 2.38 (±0.2) 1.93 (±0.4) 0.45 (0.3 to 0.6)d
Operating time (min) 7.15 [4.51 – 11.84] 5.80 [2.61 – 9.89]
Operating timec 2.62 (±0.4) 2.51 (±0.4) 0.1 (-0.02 to 0.2)d
Procedure time (min) 11.62 [9.08 – 15.36] 8.00 [3.96 – 12.00]
Procedure timec 2.85 (±0.3) 2.66 (±0.3) 0.2 (0.1 to 0.3)d
Total number of insertions of the
hysteroscope/ cannula -70.7 (-82.9 to -58.6) b
1 61 (87.1) 10 (16.4)
≥2 9 (12.9) 51 (83.6)

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Conversion rate 4.2 (-1.5 to 10)b

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EVA to HM 0 (0) 1 (1.3)
HM to EVA 4 (5.5) 0 (0)
Intraoperative complications
Hemorrhage (> 500 mL)
4 (5.5)
1 (1.4)
-p 4 (5.0)
1 (1.3)
0.5 (-6.6 to 7.6)b
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Perforation during dilation 2 (2.7) 0 (0)
Perforation during surgery 0 (0) 3 (3.8)
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Fluid deficit > 2500ml 1 (1.4) 0 (0)

Hospitalized > 1 day 0 (0) 1 (1.3) -1.3 (-3.8 to 1.2)b
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CI = confident interval; EVA = electric vacuum aspiration; HM = hysteroscopic morcellation

a
Data are mean ±standard deviation, median (interquartile range [25% - 75%], or n (%) unless
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otherwise specified. Percentage excluded patients with missing values.

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b
Absolute risk differences and 95% CIs were estimated.
c
Times shown are log transformed data.
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d
Absolute differences and 95% CIs were estimated on log transformed data.
Table 3: Primary outcomea
HM (63)# EVA (64)# Difference (95% CI) P value
b
Presence of IUAs* 9 (14.3) 13 (20.6) -6 (-19.1 to 7.1) .348
Mild 4 (44.4) 3 (23.1)
Moderate 3 (33.3) 6 (46.2)
Severe 2 (22.2) 4 (30.8)
CI = confident interval; EVA = electric vacuum aspiration; IUAs = intrauterine adhesions; HM =
hysteroscopic morcellation;
a
Data are mean ±standard deviation, median (interquartile range [25% - 75%], or n (%) unless
otherwise specified. Percentage excluded patients with missing values. All P values are from Chi-
Square test unless otherwise specified.
b
Absolute risk differences and 95% CIs were estimated.
#
The number of patients who underwent second-look procedure.

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* Presence of IUAs as diagnosed with second-look hysteroscopy after at least 1 menstruation or after

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a minimum period of 4 weeks after removal of the placental remnants.

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Table 4: Postoperative coursea
HM (73) EVA (80) Difference (95% CI)
Postoperative complications 2 (2.7) 1 (1.3) 1.4 (-3.1 to 6)b
Hemorrhage (>500cc) 2 (2.7) 0 (0)
Other 0 (0) 1 (1.3)
Rehospitalization 2 (3.1) 1 (1.5) 1.2 (-3.5 to 6.0)b
Second look hysteroscopy performed 63 (86.3) 64 (80) 6.3 (-5.5 to 18.1)b
Completeness of removal at second
look hysteroscopy 60 (95.2) 52 (82.5) -14 (-24.9 to -3.1)b
Additional treatment 8 (12.5) 21 (32.8) -20.1 (-34.3 to -6)b
Operative hysteroscopy 8 (12.5) 21 (32.8)
For RPOC 3 (4.7) 9 (14.1)
For IUAs 6 (9.4) 13 (20.3)

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Vacuum curettage 1(1.6) 0 (0)
Laparoscopic repair 0 (0) 1 (1.6)

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CI = confident interval; EVA = electric vacuum aspiration; IUAs = intrauterine adhesions; HM =
hysteroscopic morcellation; RPOC = retained products of conception
a -p
Data are mean ±standard deviation, median (interquartile range [25% - 75%], or n (%) unless
otherwise specified. Percentage excluded patients with missing values.
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b
Absolute risk differences and 95% CIs were estimated.
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