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Endometriosis: From Diagnosis to Implantation and Pregnancy Lier, M.C.I.

2021

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Download date: 06. Oct. 2021 Endome triosis From Diagnosis to Implantation and Pregnancy

Marit C.I. Lier Marit C.I. Lier Endometriosis: From diagnosis to implantation and pregnancy By Marit C.I. Lier

ISBN: 978-94-6416-184-7 Cover design & layout: Sanne Kassenberg | persoonlijkproefschrift.nl Printing: Ridderprint | www.ridderprint.nl

Financial support for printing of this thesis was kindly provided and supported by: Bridea Medical BV, Chipsoft, Endometriose Stichting, Ferring BV, Gedeon Richter, Goodlife Pharma, Guerbet, ICT Healthcare Technoloy Solutions BV, IQ Medical Ventures BV, Memidis Pharma BV and the VU University Amsterdam A digital version of this thesis can be found on research.vumc.nl Copyright © 2020 by Marit C.I. Lier. All rights reserved. No parts of this thesis may be reproduced, stored or transmitted in any way without prior permission of the author. VRIJE UNIVERSITEIT

ENDOMETRIOSIS: FROM DIAGNOSIS TO IMPLANTATION AND PREGNANCY

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctor aan

de Vrije Universiteit Amsterdam,

op gezag van de rector magnificus

prof.dr. V. Subramaniam,

in het openbaar te verdedigen

ten overstaan van de promotiecommissie

van de Faculteit der Geneeskunde

op vrijdag 15 januari 2021 om 9.45 uur

in de aula van de universiteit,

De Boelelaan 1105

door

Marit Cathérine Isabelle Lier

geboren te Nieuwegein promotoren: prof.dr. V. Mijatovic prof.dr. C.B. Lambalk promotiecommissie: prof.dr. C.J.M. de Groot prof.dr. C. Tomassetti prof.dr. F.W. Jansen prof.dr. K.W.M. Bloemenkamp prof.dr. A.W. Nap dr. E. Moll CONTENTS

Chapter 1 General introduction and outline of this thesis 9

PART I Pathophysiological aspect of 27 endometriosis; enhancement of surgical diagnosis and fertility treatment

Chapter 2 Laparoscopic imaging techniques in endometriosis therapy: 29 a systematic review Vlek S.L., Lier M.C.I., Ankersmit M., Ket J.C.F., Dekker J.J.M.L., Mijatovic V., Tuynman J.B. J. Minim Invasive Gynecol. 2016;23:886-892.

Chapter 3 Comparison of enhanced laparoscopic imaging techniques 49 in endometriosis surgery: a diagnostic accuracy study Lier M.C.I., Vlek S.L., Ankersmit M., van de Ven P.M., Dekker J.J.M.L., Bleeker M.C.G., Mijatovic V., Tuynman J.B. Surg Endosc. 2020;34:96-104.

Chapter 4 Continuous oral contraceptives versus long-term pituitary 67 desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial Lier M.C.I., van der Houwen L.E.E., Schreurs A.M.F., van Wely M., Hompes P.G.A., Cantineau A.E.P., Schats R., Lambalk C.B., Mijatovic V. Hum Reprod Open. 2019;2019:1-8.

Chapter 5 Uterine bathing with sonography gel prior to IVF/ICSI- 85 treatment in patients with endometriosis, a multicenter randomized controlled trial Lier M.C.I., Özcan H., Schreurs A.M.F., van de Ven P.M., Dreyer K., van der Houwen L.E.E., Johnson N.P., Vandekerckhove F., Verhoeve H.R., Kuchenbecker W., Mol B.W., Lambalk C.B., Mijatovic V. Accepted for publication Hum Reprod Open. PART II Pathophysiological aspect of endometriosis 105 in pregnancy

Chapter 6 Spontaneous haemoperitoneum in pregnancy and 107 endometriosis; a case series Lier M.C.I., Malik R.F., van Waesberghe J.H.T.M., Maas J.W., van Rumpt- van de Geest D.A., Coppus S.F., Berger J.P., van Rijn B.B., Janssen P.F., de Boer M.A., de Vries J.I.P., Jansen F.W., Brosens I.A., Lambalk C.B., Mijatovic V. BJOG. 2017;124:306-312.

Chapter 7 Spontaneous hemoperitoneum in pregnancy (SHiP) and 121 endometriosis – a systematic review of the recent literature Lier M.C.I., Malik R.F., Ket J.C.F., Lambalk C.B., Brosens I.A., Mijatovic V. Eur J Obstet Gynecol Reprod Biol. 2017;219:57-65.

Chapter 8 Severe spontaneous hemoperitoneum in pregnancy may be 143 linked to in vitro fertilization in patients with endometriosis: a systematic review Brosens I.A., Lier M.C.I., Mijatovic V., Habiba M., Benagiano G. Fertil Steril. 2016;106:692-703.

Chapter 9 Decidual bleeding as a cause of spontaneous hemoperitoneum 167 in pregnancy and risk of preterm birth Lier M.C.I., Brosens I.A., Mijatovic V., Habiba M., Benagiano G. Gynecol Obstet Invest. 2017;82:313-321.

Chapter 10 Summary 187 General discussion and future perspectives 191

Appendices Nederlandse Samenvatting 206 PhD portfolio 210 List of publications 212 List of co-authors 214 Dankwoord 218 Over de auteur 222

CHAPTER 1

General introduction and outline of this thesis Chapter 1

GENERAL INTRODUCTION

Here we discuss the background of endometriosis and provide insight in the etiology, diagnosis and treatment of this disease.

Endometriosis is a common benign gynaecological disorder. It is defined as the presence of endometrial-like tissue (glands and stroma) outside the uterine cavity, growing under the influence of estrogens, where it induces a chronic inflammatory reaction [1,2]. The exact prevalence of endometriosis in the general population is not known and difficult to determine due to a wide variety in symptoms. Estimates range from 2 to 10% in women of reproductive age, and up to 50% in women presenting with infertility or chronic pelvic pain [3,4]. An estimated likely prevalence of 176 million women worldwide suffer from endometriosis with substantial individual and socioeconomic burden [5-7].

The presence of intra-abdominal endometriosis can be suspected based on women’s medical history and clinical symptoms like dysmenorrhea, dyschezia, heamatochezia, dysuria, haematuria, dyspareunia and chronic pelvic pain [8]. Complaints are often related to the menstrual cycle and are progressive in nature. However, symptoms can also be very mild or women can even be asymptomatic. Although endometriosis can be suspected based on presenting symptoms and signs, findings by physical examination and imaging modalities (e.g., transvaginal ultrasound (TVU) and magnetic resonance imaging (MRI)), surgical identification and histological verification of endometriotic tissue remain the gold standard for the definitive diagnosis [8]. Even in women without any symptoms, endometriosis can be diagnosed during fertility work-up or as coincidental finding during abdominal surgery. In general, it can be stated that clinical symptoms and patients’ experience poorly reflect the severity of the disease [9-11].

ETIOLOGY OF ENDOMETRIOSIS The exact etiology and pathogenesis of endometriosis is nowadays still poorly understood. Microscopic findings of endometriosis were first described by von Rokitansky in 1860 [12]. Followed by Diesterweg (1883) [13], Cullen (1896) [14] and Russel (1899) [15]. In the 1920s John Sampson was the first to postulate that endometriosis originated from retrograde menstruations, disseminating endometrial tissue fragments and menstrual debris trough the fallopian tubes into the abdominal cavity [16,17]. Still, this is the most widely accepted theory regarding the etiology of endometriosis, although it does not fully explain the existence of endometriosis outside the peritoneal cavity. Besides, 76 to 90% of women have some degree of retrograde menstruation [18], but only a small part develops endometriosis. Furthermore evidence exists that dissemination of endometrial stem/progenitor cells can already occur early in life during the neonatal endometrial shedding shortly after birth or even earlier during

10 embryogenesis [19,20]. It is therefore likely that the pathogenesis of endometriosis consists of a complex multifactorial process of genetic, environmental, immunological and hormonal factors [8].

DIAGNOSIS OF ENDOMETRIOSIS Abdominal endometriosis can be classified in superficial (peritoneal) endometriosis, deep infiltrating (pelvic) endometriosis and ovarian endometriosis.

Superficial or peritoneal endometriosis is defined as the presence of deposits of 1 endometrial glands and stroma on the pelvic peritoneal surface and ovaries. They can induce an inflammatory reaction resulting in pelvic pain complaints and formation of adhesions in the abdominal cavity. Peritoneal lesions can only be visualized during laparoscopy and is largely depending upon the experience of the surgeon performing the inspection. However, even for experienced surgeons it remains hard to distinguish non-pigmented endometriotic lesions from healthy peritoneal tissue [21-24]. Moreover, persistent or recurrent endometriosis complaints after surgical treatment occur in almost 50% of the cases in a period up to 5 years postoperatively. Data from a prospective study show that this recurrence occurs mainly in the treated area and that endometriosis de novo only accounts for 11% of the recurrence in second- look laparoscopy [25,26]. The intraoperative use of enhanced laparoscopic imaging techniques might improve the identification and treatment of peritoneal endometriosis and will be further evaluated in this thesis.

Ovarian endometriosis or endometriomas are cysts formed by deposits of endometriosis within the ovary. They originate from pseudocysts that are formed by invagination of endometriotic tissue within the ovarian cortex [27,28]. It is diagnosed in 17 to 44% of women with endometriosis [29], and are more frequently seen in women with concomitant deep endometriosis [30].

Deep endometriosis is defined as endometriotic lesions extending more than 5 mm under the peritoneal surface or involving bowel, bladder, ureter or vagina [31,32]. Often deep endometriosis appears as nodular lesions or plaques consisting of active endometrial-like glands and cytogenous stroma, smooth muscle cells and fibrosis [33].

Finally, endometriosis can also be found outside the pelvic area at a distance from the genital organs, and involve the upper abdomen, diaphragm, pleura, lungs, sciatic nerve as well as the abdominal wall.

Clinical presentation Although presenting symptoms often depend on the location of the disease, the wide variety of clinical symptoms can also lead to difficulties in establishing the final

11 Chapter 1 diagnosis of endometriosis. This results in many women receiving either delayed or suboptimal care [2]. Dysmenorrhea seems to be the most reported complaint (62%) followed by chronic pelvic pain (57%), dyspareunia (55%), (cyclic) intestinal complaints (48%), (cyclic) urinary complaints (12%) and subfertility (40%) [34]. In subfertile women severe dysmenorrhea was the only predictive symptom for the presence of pelvic endometriosis with a relative risk of 1.7 [35].

Physical examination Physical examination is essential in women suspected to have endometriosis and is aimed to facilitate a timely diagnosis. However, the absence of any abnormalities during physical examination cannot rule out the presence of endometriosis. Physical examination includes inspection and (bimanual) palpation of the abdomen, vagina, cervix, fornices, internal genital organs and rectovaginal septum. Rectovaginal digital examination can be considered when involvement of the rectosigmoidal colon is suspected [36]. Physical examination performed during menstruation increases the chances of finding pelvic nodularities and was reliable to diagnose deep endometriosis, endometriomas and cul-de-sac adhesions [37]. However, the benefit of physical examination is limited since it is less accurate than imaging modalities for the assessment of deep endometriosis and ovarian endometriomas [36,38,39]. Besides, the quality of the examination is determined by the experience and skills of the clinician.

Imaging The most frequently used imaging modalities for the detection of endometriosis are transvaginal ultrasound (TVU) and magnetic resonance imaging (MRI).

TVU is a first line non-invasive imaging tool and especially useful for the identification of bowel and bladder endometriosis [40], ovarian endometriomas as well as adenomyosis [41,42]. TVU evaluation is accompanied with high sensitivity and specificity rates when performed by experienced clinicians. However, since endometriomas are rarely a solitary finding, one should be thoughtful for the simultaneous existence of more extensive pelvic and intestinal disease [43]. Therefore further examination with MRI can be considered [8]. MRI has a high diagnostic accuracy and can especially be used to assess the extent of the disease, in women with deep endometriosis, and provide mapping and guidance for surgical treatment [44].

Biomarkers The use of serum CA-125 as a biomarker for endometriosis seems to be of limited value. Serum CA-125 has low diagnostic performance and is currently not advised to be used to diagnose endometriosis [8,45,46]. Up till now, no reliable biomarkers, (in serum, urine and endometrium) are available for the non-invasive detection of

12 endometriosis [47]. Therefore, laparoscopy is still the gold standard test for the diagnosis of the disease.

TREATMENT OF ENDOMETRIOSIS

Hormonal treatment Since endometriosis is an estrogen-dependent disease, hormonal suppression of the menstrual cycle is the key factor in the medical treatment of endometriosis. By shared decision making, clinicians can prescribe multiple hormonal treatment options, 1 taking into account patients’ preferences, side-effects, efficacy, costs and availability [8]. Hormonal contraceptives, progestogens, anti-progestogens or GnRH agonist/ antagonists are all proven to reduce endometriosis-related pain complaints [48-51]. A continuous regime of a combined oral contraceptive pill can be considered if women suffer from severe dysmenorrhea or in order to prevent recurrence of endometriomas after surgery [52,53].

Surgical treatment Laparoscopic identification and histological verification of endometriotic tissue remain the gold standard for the final diagnosis of the disease [8]. Treatment of symptomatic endometriosis, especially when not responding to hormonal treatment, consists of laparoscopic excision or ablation of endometriotic tissue [8]. Laparoscopic treatment of mild and moderate endometriosis reduces pain complaints and increases ongoing pregnancy and live birth rate [54]. Therefore it is advised to treat all visible endometriosis during laparoscopy rather than performing only a diagnostic procedure [8]. Surgical removal of severe/deep endometriosis seems to be effective in reducing pain complaints and improves quality of life, although it is associated with significant complications and recurrence rates [55,56]. Surgical treatment of endometriosis can be combined with adhesiolysis in order to restore pelvic anatomy, possibly reducing endometriosis-related pain and enhancing fertility [57].

Although a negative diagnostic laparoscopy is accurate for excluding the disease, a positive laparoscopy is of less value especially when no histology is obtained [58]. Previous studies reported a low positive predictive value of 2D white-light laparoscopy of only 66% [59]. Therefore, complete resection of endometriosis is a challenge and re-operation, due to symptomatic recurrence, occurs in more than 50% of the patients [25,60]. The polymorphic appearance of especially non-pigmented endometriotic lesions is supposed to be the origin of this impaired visual diagnosis during laparoscopy [21-23]. The quality of laparoscopic surgical treatment is therefore dependent upon the experience of the surgeon performing the procedure.

13 Chapter 1

ENDOMETRIOSIS AND SUBFERTILITY Endometriosis is associated with subfertility in up to 50% of patients [4]. Although the association is clear, the link between endometriosis and subfertility is largely unknown. A multifactorial process is assumed. In patients with severe endometriosis, subfertility is probably related to a distortion of the pelvic anatomy. However, a hostile peritoneal environment, diminished ovarian reserve (due to the presence of endometriomas or as a consequence of prior ovarian surgery), decreased oocyte quality and/or an impaired implantation due to an altered endometrial receptivity may be other explanations for the lower chances to conceive in women with endometriosis [61,62]. It is however remarkable that a correlation between the severity of endometriosis and pregnancy rates cannot be found [32, 63].

Treatment of endometriosis related subfertility is challenging and high quality evidence on this subject is limited. Van der Houwen recently proposed a treatment algorithm for subfertility in women with endometriosis [57]. In this algorithm patients with any stage of endometriosis are assigned to different strategy boxes (natural conception, IUI with COH of IVF/ICSI) depending on the need for hormonal suppression therapy, patency of the fallopian tubes, presence of endometriosis related pain complaints and the chances on progression of the disease. In women who received surgical treatment for endometriosis, the endometriosis fertility index (EFI) score can be used as a validated scoring system that predicts spontaneous pregnancy rates in postoperative endometriosis patients or it may act as an instrument for Assisted Reproductive Technology (ART) referral [64]. Although ART is frequently applied to overcome endometriosis-related infertility, lower success rates have been reported [65]. Whether pregnancy outcomes after IVF/ICSI can be improved by medical or surgical pretreatment, or applying interventions that affect endometrial receptivity, is not well established.

Medical pretreatment The role of medical treatment of endometriosis prior to IVF/ICSI is still a matter of debate. Traditionally it was recommended to precede IVF/ICSI treatment in endometriosis patients by long term pituitary desensitization with a GnRH agonist for three to six months to increase the chance of clinical pregnancy, either by improving oocyte quality or endometrial receptivity [66-74]. However uncomfortable side effects were reported and a lower ovarian response to ovarian stimulation has been mentioned [75]. Besides, the recent Cochrane systematic review reporting on this topic concluded to be uncertain whether GnRH agonist pretreatment indeed positively affects IVF/ ICSI outcomes [76]. Based on eight randomized controlled trials, including a total of 640 women, no convincing evidence of pretreatment with a long-term GnRH agonist was found. Moreover, no comparison with alternative treatment strategies have been made yet. The authors concluded that high-quality trials are required to determine the effect of pre-treatment with a long-term GnRH agonist in endometriosis patients prior

14 to IVF/ICSI and the comparison with other alternatives must be made [76]. For this reason the COPIE trial was conducted, investigating the efficacy of long-term pituitary desensitization with a GnRH agonist in comparison to oral contraceptives prior to IVF/ ICSI treatment in women with moderate to severe endometriosis (Chapter 4).

Endometrial receptivity It has been hypothesized that local endometrial injury might have a beneficial effect on endometrial receptivity and implantation [77,78]. This is especially of interest for women with endometriosis or recurrent implantation failure after IVF/ICSI. The 1 mechanisms behind the effect of applying endometrial injury are still unclear, though there are different hypotheses. The inflammatory reaction following endometrial injury, mainly executed by endometrial scratching, stimulates decidualization of endometrial stromal cells and leads to a release of cytokines and growth factors [79-82]. In addition, it is suggested that the advanced and accelerated development of the endometrium, induced by ovarian hyperstimulation during IVF/ICSI-treatment, is delayed by applying endometrial injury and consequently improves the receptivity of the endometrium [81]. As an alternative to scratching, the receptivity of the endometrium might also be affected by infusing fluids into the uterine cavity (“uterine bathing”). Previous studies investigating the effect of uterine bathing with Lipiodol® suggested a positive effect on endometrial receptivity by immunomodulation [83-86]. The effect of mechanical stress on endometrial receptivity by uterine bathing with a pharmacologically neutral gel will be evaluated in this thesis (Chapter 5).

ENDOMETRIOSIS IN PREGNANCY Traditionally, it is believed that pregnancy has a favorable influence on endometriosis. The blockage of ovulation, the concomitant amenorrhea and the metabolic, hormonal, immune and angiogenetic changes are supposed to prevent endometriotic lesions from bleeding and expanding in pregnancy [87-91]. Patients do experience less endometriosis-related complaints during and directly after pregnancy; however, symptoms rapidly recur with 84% of patients reporting moderate-severe pain symptoms within 2 years after pregnancy [92]. The negative influence of endometriosis on pregnancy is currently a growing area of concern. Recent literature reviews point out to a wide spectrum of negative obstetrical events possibly related to pre-existing endometriosis and adenomyosis [91,93]. Most complications are rare, but some, like Spontaneous Hemoperitoneum in Pregnancy (SHiP) are potentially life-threatening. Awareness among physicians for endometriosis associated obstetrical complications must be increased and therefore SHiP, and its clinical features, are important issues in this thesis and will be evaluated.

Endometriosis-related complications in pregnancy can be two-fold. On the one hand acute complications can occur from pre-existing endometriosis, on the other hand

15 Chapter 1 endometriosis might have a negative impact on the physiological development of a pregnancy [91].

The involvement of endometriosis in acute pregnancy complications can be explained by the following pathogenic mechanisms; 1) Utero-ovarian vessels and surrounding tissues may be more friable due to the chronic inflammation that is associated with endometriosis [94,95]; 2) Pelvic adhesions (related to endometriosis or as a resultant of previous abdominal surgery) in combination with an enlargement of the uterus during pregnancy can give more tension to surrounding tissue [94,96]; 3) Mechanical obstruction by invasions of decidualized endometriotic tissue into vessel walls and structures increases pressure and facilitates tissue rupture [97]. Besides, decidualized ectopic endometrium near utero-ovarian of parametrial vessels can involute due to progesterone withdrawal and lead to dysfunctional rupture of such vessels [98,99].

SHiP is defined as a “spontaneous (nontraumatic) intraperitoneal hemorrhage during pregnancy and up to 42 days postpartum, requiring surgical intervention or embolization” with exclusion of ectopic pregnancy-, uterine rupture- and caesarean section associated bleedings [100]. Although the exact prevalence is unknown, estimates range around 0.4% in pregnancy [101]. SHiP occurs predominantly in the third trimester of pregnancy and is associated with serious adverse pregnancy outcomes [98,102]. Other complications described in pregnancy are intestinal perforations, complications from ovarian endometriomas (rupture, infection or enlargement), urinary tract problems, uterine rupture and endometriotic involvement in thoracic organs leading to a pneumothorax [91,93]. Although cases are rare, and preventive measures are lacking, diagnosis should be considered when patients with known endometriosis present with acute (pelvic/chest) pain and/or signs of (hypovolemic) shock in pregnancy.

The negative role endometriosis can have on the development of pregnancies is still controversial. Pregnancy complications might be caused by a dysregulation of events that are involved in the period of implantation and placentation [91], leading to disturbances later in pregnancy [103]. Although the growing number of papers reporting on the relation between endometriosis and adverse obstetric outcomes, an association with ectopic pregnancies and placenta praevia seems present [91,93,104,105]. There is no convincing evidence of an association between endometriosis and miscarriages, preterm births, hypertensive disorders, obstetric hemorrhages, SGA (small for gestational age) babies and GDM (gestational diabetes mellitus) [91,93].

There is no evidence that hormonal or surgical treatment of endometriosis prior to pregnancy lowers the risk of obstetrical complications.

16 SCOPE OF THIS THESIS

In this thesis we aim to gain insight in the pathophysiological aspect of endometriosis. This thesis consists of two parts; PART I) Pathophysiological aspects of endometriosis; enhancement of surgical diagnosis and fertility treatment PART II) Pathophysiological aspects of endometriosis in pregnancy

This thesis addresses the following questions: 1

PART I) 1. Which enhanced laparoscopic imaging techniques are published for the intraoperative identification of peritoneal endometriosis? 2. Which enhanced laparoscopic imaging technique is the most accurate for the detection of peritoneal endometriosis? 3. What is the efficacy of long-term pituitary desensitization with a GnRH agonist in comparison to oral contraceptives prior to IVF/ICSI treatment in women with moderate to severe endometriosis? 4. What is the effect of uterine bathing with sonography gel prior to IVF/ICSI-treatment in women with endometriosis?

PART II) 5. What are the clinical consequences of Spontaneous Hemoperitoneum in Pregnancy (SHiP) in patients with endometriosis ? 6. What is the association between SHiP and endometriosis? 7. What is the association between SHiP and IVF/ICSI-treatment? 8. What is the pathogenesis of SHiP? In particular, which pathological events are found at the site of SHiP bleeding? Pathophysiological aspects of endometriosis

Endometriosis and Endometriosis and Endometriosis and pregnancy; surgical treatment; fertility treatment; - Complications of - Use of enhanced - Medical treatment endometriosis in pregnancy? laparoscopic imaging prior to ART? - Clinical consequences of SHiP? techniques? - Uterine bathing - Endometriosis, SHiP and procedures? fertility treatment?

17 Chapter 1

OUTLINE OF THIS THESIS

In CHAPTER 2 the results of a systematic review are presented, evaluating the different enhanced laparoscopic imaging techniques that are used for the intraoperative identification of peritoneal endometriosis.

CHAPTER 3 describes the LITE study (Laparoscopic Imaging Techniques in Endometriosis therapy), a clinical trial in which different enhanced laparoscopic imaging techniques ((three-dimensional white-light imaging (3D); Narrow-Band Imaging (NBI); Near-Infrared imaging with Indocyanine Green (NIR-ICG)) for the intraoperative identification of peritoneal endometriosis were directly compared. The accuracy (sensitivity and specificity) of the modalities was investigated and compared to two-dimensional white-light imaging (2D).

CHAPTER 4 describes the study protocol of the COPIE trial (Continuous use of Oral contraceptives as an alternative for long term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients), a randomized controlled trial which will investigate the efficacy of long-term pituitary desensitization with a GnRH agonist compared to continuous use of oral contraceptives prior to IVF/ICSI treatment in women with moderate to severe endometriosis. This non-inferiority trial will investigate the efficacy, safety, cost-effectiveness and patient satisfaction of both treatment strategies.

In CHAPTER 5 the results of the TUBIE trial (Trial on Uterine Bathing before IVF/ICSI- treatment in patients with Endometriosis) are presented; a randomized controlled trial investigating the effect of uterine bathing by Gel Infusion Sonography (GIS) versus a sham procedure, prior to IVF/ICSI-treatment in women with endometriosis. The primary outcome was live birth rate after fresh embryo transfer.

In CHAPTER 6 a case-series is presented. In collaboration with the Dutch Working Group on Endometriosis, unpublished cases of SHiP that occurred in the Netherlands between 2010-2015 were retrieved. Presenting symptoms, pregnancy outcomes and implications for clinical practice are discussed.

In CHAPTER 7 a systematic review is performed to evaluate the clinical consequences of SHiP and the association with endometriosis.

CHAPTER 8 describes the results of a systematic review evaluating the evidence of a possible association between controlled ovarian hyperstimulation in IVF/ICSI- treatment and the occurrence of SHiP.

18 In CHAPTER 9 a literature search was performed in order to determine the type of lesions that lead to SHiP. For a better understanding of the pathogenesis of SHiP, information on pathological events at the site of bleeding were collected.

In the general discussion in CHAPTER 10 we discuss the findings of this thesis and add them in the context of the current literature.

1

19 Chapter 1

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20 24. Lier MCI, Vlek SL, Ankersmit M, et al. Comparison of enhanced laparoscopic imaging techniques in endometriosis surgery: a diagnostic accuracy study. Surg Endosc. 2020 Jan;34:96-104. 25. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–461. 26. Taylor E, Williams C. Surgical treatment of endometriosis: location and patterns of disease at reoperation. Fertil Steril. 2010 Jan;93:57-61. 27. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 1994;61:1034-1038. 28. Nezhat F, Nezhat C, Allan CJ, Metzger DA, Sears DL. Clinical and histologic classification of endometriomas. Implications for a mechanism of pathogenesis. J Reprod Med. 1992;37:771- 776. 29. Busacca M, Vignali M. Ovarian endometriosis: from pathogenesis to surgical treatment. Curr 1 Opin Obstet Gynecol. 2003;15:321–326. 30. Banerjee SK, Ballard KD, Writh JT. Endometriomas as a marker of disease severity. J Minim Invasive Gynecol. 2008;15:538-540. 31. Keckstein J, Ulrich U., Possover M, Schweppe KW. ENZIAN-Klassifikation der tief infiltrierenden Endometriose. Zentralbl Gynäkol. 2003;125:291. 32. Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32:315-324. 33. Anaf V, Simon P, Fayt I, Noel J. Smooth muscles are frequent components of endometriotic lesions. Hum Reprod. 2000;15:767-771. 34. Bellelis P, Dias JA Jr, Podgaec S, Gonzales M, Baracat EC, Abrão MS. Epidemiological and clinical aspects of pelvic endometriosis–a case series. Rev Assoc Med Bras (1992). 2010;56:467-71. 35. Forman RG, Robinson JN, Mehta Z, Barlow DH. Patient history as a simple predictor of pelvic pathology in subfertile women. Hum Reprod. 1993;8:53-55. 36. Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Daraï E. Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertil Steril. 2009;92:1825-1833. 37. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ. Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration. Fertil Steril. 1996;65:280-287. 38. Chapron C, Dubuisson JB, Pansini V, et al. Routine clinical examination is not sufficient for diagnosing and locating deeply infiltrating endometriosis. J Am Assoc Gynecol Laparosc. 2002;9:115-119. 39. Hudelist G, Ballard K, English J, et al. Transvaginal sonography vs. clinical examination in the preoperative diagnosis of deep infiltrating endometriosis. Ultrasound Obstet Gynecol. 2011;37:480-487. 40. Hudelist G, English J, Thomas AE, Tinelli A, Singer CF, Keckstein J. Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2011;37:257-263. 41. Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol. 2002;20:630–634. 42. Van den Bosch T, Dueholm M, Leone FP, et al. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015;46:284-298. 43. Redwine DB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999;72:310-315.

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44. Busard M. Proefschrift: Advances of MR imaging in endometriosis. 2012 45. Mol BW, Bayram N, Lijmer JG, et al. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril. 1998;70:1101–1108. 46. May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010;16:651–674. 47. Fassbender A, Burney RO, O DF, D’Hooghe T, Giudice L. Update on Biomarkers for the Detection of Endometriosis. Biomed Res Int. 2015;2015:130854. 48. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin- releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril. 1993;60:75–79. 49. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2010:CD008475. 50. Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Cochrane Database Syst Rev. 2012:CD002122. 51. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017;377:28-40. 52. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 2003;80:560–563. 53. Vercellini P, DE Matteis S, Somigliana E, Buggio L, Frattaruolo MP, Fedele L. Long-term adjuvant therapy for the prevention of postoperative endometriomas recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2013;92:8-16. 54. Duffy JMN, Arambage K, Correa FJS, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014:CD011031. 55. De Cicco C, Corona R, Schonman R, Mailova K, Ussia A, Koninckx P. Bowel resection for deep endometriosis: a systematic review. BJOG. 2011;118:285–291. 56. Meuleman C, Tomassetti C, D’Hoore A, et al. Surgical treatment of deeply infiltrating endometriosis with colorectal involvement. Hum Reprod Update. 2011;17:311–326. 57. Van der Houwen LEE. Proefschrift: endometriosis associated subfertility. 2019 58. Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG. 2004;111:1204-1212. 59. Marchino GL, Gennarelli G, Enria R, Bongioanni F, Lipari G, Massobrio M. Diagnosis of pelvic endometriosis with use of macroscopic versus histologic findings. Fertil Steril. 2005;84:12–15. 60. Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: How often do we need to re-operate? J Obstet Gynaecol: the J Inst Obstet Gynaecol. 2008;28:82–85. 61. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362:2389-2398. 62. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376:730-738. 63. Adamson GD. Endometriosis classification: an update. Curr Opin Obstet Gynecol. 2011;23:213- 220. 64. Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2010;94:1609-1615. 65. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148-1155. 66. Dicker D, Goldman GA, Ashkenazi J, Feldberg D, Voliovitz I, Goldman JA. The value of pre- treatment with gonadotrophin releasing hormone (GnRH) analogue in IVF-ET therapy of severe endometriosis. Hum Reprod. 1990;5:418-420.

22 67. Dale PO, Tanbo T, Abyholm T. Endometriosis-associated infertility treated by long-term gonadotropinreleasing hormone agonist administration and assisted fertilization. J In Vitro Fert Embryo Transf. 1990;7:180-181. 68. Dicker D, Goldman JA, Levy T, Feldberg D, Ashkenazi J. The impact of long-term gonadotropinreleasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer. Fertil Steril. 1992;57:597- 600. 69. Nakamura K, Oosawa M, Kondou I, et al. Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis. J Assist Reprod Genet. 1992;9:113-117. 70. Chedid S, Camus M, Smitz J, Van Steirteghem AC, Devroey P. Comparison among different 1 ovarian stimulation regimens for assisted procreation procedures in patients with endometriosis. Hum Reprod. 1995;10:2406-2411. 71. Rickes D, Nickel I, Kropf S, Kleinstein J. Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis. Fertil Steril. 2002;78:757-762. 72. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin- releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002;78:699-704. 73. Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006:CD004635. 74. Ma C, Qiao J, Liu P, Chen G. Ovarian suppression treatment prior to in-vitro fertilization and embryo transfer in Chinese women with stage III or IV endometriosis. Int J Gynaecol Obstet. 2008;100:167-170. 75. Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and metaanalysis. Fertil Steril. 2008;90:1055-1063. 76. Georgiou EX, Melo P, Baker PE, et al. Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis. Cochrane Database Syst Rev. 2019:CD013240. 77. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25:561-71. 78. Nastri CO, Lensen SF, Gibreel A, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2015:CD009517. 79. Dekel N, Gnaisky Y, Granot I, Mor G. Inflammation and Implantation. Am J Reprod Immunol. 2010;63:17-21. 80. Gnaisky Y, Granot I, Aldo PB, et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantatnion. Fertil Steril. 2010;94:2030-2036. 81. Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril. 2008;89:1166-1176. 82. Li R, Hao G. Local injury to the endometrium: its effect on implantation. Curr Opin Obstet Gynecol. 2009;21:236-239. 83. Johnson NP, Farquhar CM, Hadden WE, Suckling J, Yu Y, Sadler L. The FLUSH trial--flushing with lipiodol for unexplained (and endometriosis-related) subfertility by hysterosalpingography: a randomized trial. Hum Reprod. 2004;19:2043-2051. 84. Johnson NP, Bhattu S, Wagner A, Blake DA, Chamley LW. Lipiodol alters murine uterine dendritic cell populations: a potential mechanism for the fertility-enhancing effect of lipiodol. Fertil Steril. 2005;83:1814-1821.

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85. Johnson NP. Review of lipiodol treatment for infertility - an innovative treatment for endometriosis-related infertility? Aust N Z J Obstet Gynaecol. 2014;54:9-12. 86. Johnson NP, Baidya S, Jessup SO, et al. Randomised trial of Lipiodol Uterine Bathing Effect (LUBE) in women with endometriosis-related infertility. Fertil Reprod. 2019;1:57-64. 87. Beecham CT. Surgical treatment of endometriosis with special reference to conservative surgery in young women. J Am Med Assoc. 1949;139:971. 88. Kistner RW. Conservative management of endometriosis. Lancet. 1959;79:179–183. 89. Kistner RW. Endometriosis and infertility. Clin Obstet Gynecol. 1959;2:877–889. 90. Moen MH, Muus KM. Endometriosis in pregnant and nonpregnant women at tubal sterilization. Hum Reprod. 1991;6:699-702. 91. Leone Roberti Maggiore U, Ferrero S, Mangili G, et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. Hum Reprod Update. 2016;22:70-103. 92. Alberico D, Somigliana E, Bracco B, et al. Potential benefits of pregnancy on endometriosis symptoms. Eur J Obstet Gynecol Reprod Biol. 2018;230:182-187. 93. Vigano P, Corti L, Berlanda N. Beyond infertility: obstetrical and postpartum complications associated with endometriosis and adenomyosis. Fertil Steril. 2015;104:802-812. 94. Inoue T, Moriwaki T, Niki I. Endometriosis and spontaneous rupture of utero-ovarian vessels during pregnancy. Lancet. 1992;340:240-241. 95. Manresa MC, Godson C, Taylor CT. Hypoxia-sensitive pathways in inflammation-driven fibrosis. Am J Physiol Regul Integr Comp Physiol. 2014;307:R1369–1380. 96. Rossman F, D’Ablaing GIII, Marrs RP. Pregnancy complicated by ruptured endometrioma. Obstet Gynecol. 1983;62:519–521. 97. O’Leary SM. Ectopic decidualization causing massive postpartum intraperitoneal hemorrhage. Obstet Gynecol. 2006;108:776–779. 98. Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril. 2009;92:1243-1245. 99. Erikson DW, Chen JC, Piltonen TT, Conti M, Irwin JC, Giudice LC. Inhibition of epidermal growth factor receptor restores decidualization markers in stromal fibroblasts from women with endometriosis. J Endometriosis. 2014;6:196–211. 100. Schaap T, Bloemenkamp K, Deneux-Tharaux C, et al. Defining definitions: a Delphi study to develop a core outcome set for conditions of severe maternal morbidity. BJOG. 2019;126:394- 401. 101. Katorza E, Soriano D, Stockheim D, et al. Severe intraabdominal bleeding caused by endometriotic lesions during the third trimester of pregnancy. Am J Obstet Gynecol. 2007;197:501.e1-504. e5014. 102. Lier MCI, Malik RF, Ket JCF, Lambalk CB, Brosens IA, Mijatovic V. Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - A systematic review of the recent literature. Eur J Obstet Gynecol Reprod Biol. 2017;219:57-65. 103. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18:1754–1765. 104. Hjordt Hansen MV, Dalsgaard T, Hartwell D, Skovlund CW, Lidegaard O. Reproductive prognosis in endometriosis. A national cohort study. Acta Obstet Gynecol Scand. 2014;93:483-489. 105. Saraswat L, Ayansina DT, Cooper KG, et al. Pregnancy outcomes in women with endometriosis: a national record linkage study. BJOG. 2017;124:444-452.

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25

Part I

Pathophysiological aspects of endometriosis; enhancement of surgical diagnosis and fertility treatment

CHAPTER 2

Laparoscopic imaging techniques in endometriosis therapy: a systematic review

Vlek, S.L. Lier, M.C.I. Ankersmit, M. Ket, J.C.F. Dekker, J.J.M.L. Mijatovic, V. Tuynman, J.B.

J. Minim Invasive Gynecol. 2016;23:886-892 Chapter 2

ABSTRACT

Endometriosis is a common disease associated with pelvic pain and subfertility. Laparoscopic surgical treatment has proven efficacy in endometriosis therapy, but is hampered by a high rate of recurrence. The aim of this systematic review was to evaluate the intraoperative identification of endometriosis by enhanced laparoscopic imaging techniques, focusing on sensitivity and specificity. A systematic review was conducted according to PRISMA guidelines in PubMed, Embase, Cochrane Library and Web of Science. Published prospective studies reporting on enhanced laparoscopic imaging techniques during endometriosis surgery were included. General study characteristics and reported outcomes, including sensitivity and specificity, were extracted. Nine studies were eligible for inclusion. Three techniques were described: 5-ALA fluorescence (5-ALA), autofluorescence (AFI), and narrow-band imaging (NBI). The reported sensitivity of 5-ALA and AFI for identifying endometriosis ranged from 91% to 100%, compared with 48% to 69% for conventional white light laparoscopy (WL). A randomized controlled trial comparing NBI+WL with WL alone reported better sensitivity of NBI (100% vs 79%; p <.001). All 9 studies reported an enhanced detection rate of endometriotic lesions with enhanced imaging techniques. Enhanced imaging techniques are a promising additive for laparoscopic detection and treatment of endometriosis. The 5-ALA, AFI and NBI intraoperative imaging techniques had a better detection rate for peritoneal endometriosis compared with conventional WL laparoscopy. None of the studies reported clinical data regarding outcomes. Future studies should address long-term results, such as quality of life, recurrence, and need for reoperation.

30 INTRODUCTION

Endometriosis is a benign, chronic, estrogen-dependent gynecologic disorder. Patients are considered for laparoscopic treatment when hormonal treatment is unsatisfactory [1,2]. Despite the proven efficacy of laparoscopic surgery, the recurrence of pain symptoms after surgery remains a major challenge and a crucial issue in the long-term management of endometriosis. The current relapse rate is >20% at 2 years and 40% to 50% at 5 years [3]. The need for hospital admission for endometriosis within 4 years after laparoscopic surgery for additional surgical treatment is 27% [4] and reoperation is necessary in >50% of patients with endometriosis, of whom 27% need 3 or more surgeries [5]. Because repeated abdominal surgery is associated with substantial 2 morbidity, damage to ovarian reserve and increased health care costs [6,7], the need for improved long-term outcomes is being emphasized.

Laparoscopic identification of endometriotic lesions is limited. During conventional laparoscopy, the detection of endometriosis with white light (WL) in suspected lesions is poor, as demonstrated by a histological study showing a positive predictive value of only 66% in suspected lesions [8]. The revised American Society for Reproductive Medicine classification system distinguishes among red, white and black superficial implant types [9]. In particular, the appearance of red and white superficial implant types can vary widely and they may be difficult to distinguish from healthy peritoneum [10]. Previous reports have shown that red and white areas of endometriosis represent the active form of the disease [11].

Enhanced laparoscopic imaging techniques have been shown to improve the detection and differentiation of specific tissues compared with conventional imaging in other fields of surgery [12–18]. These novel techniques also have the potential to improve the detection of, and potentially improve the treatment of patients with, symptomatic endometriosis.

As with (pre)malignant lesions, neovascularization is an important aspect of the pathology of endometriosis and may be helpful in identifying endometriotic lesions. A novel technique using narrow-band imaging (NBI) has been shown to enhance the contrast of vascularized lesions in premalignant gastrointestinal polyps [18]. In NBI, only blue light and green light are excited, allowing articulated visualization of superficial vasculature. In addition, the penetration depth of NBI is deeper than that of conventional WL, enabling identification of deeper lesions.

A second promising imaging technique is autofluorescence (AFI), which is based on blue light excitation and reflection of green light [14]. Owing to differences in epithelial thickness and neovascularization, different amounts of green light are reflected, resulting in color differentiation between endometriotic and non-endometriotic tissues.

31 Chapter 2

A third new imaging technique is 5-aminolevulinic acid induced fluorescence (5- ALA) [12,13]. 5-ALA is an orally administered prodrug that induces the synthesis and accumulation of protoporphyrin IX in epithelial and damaged tissue. When blue light is excited, 5-ALA is fluorescently illuminated. Patients cannot be exposed to direct sunlight within 24 hours after administration of 5-ALA because of photosensitization of the eyes and skin.

A more recently developed technique is near-infrared imaging (NIR) with indocyanine green (ICG) [16], a green iodine-based dye that has a peak fluorescent absorption in the near-infrared spectrum. ICG is administered intravenously during surgery in the arterial phase, highlighting the peritoneal vasculature. ICG is a Food and Drug Administration– approved drug associated with a very low risk of inducing an anaphylactic reaction, which has been reported exclusively in patients with iodine allergy, hyperthyroidism, or kidney failure.

In this review, we evaluated the available literature reporting on intraoperative identification of endometriosis by enhanced laparoscopic imaging techniques, focusing on the sensitivity and specificity of the different modalities.

METHODS

A review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [19]. For this work, Institutional Review Board approval was not required.

LITERATURE SEARCH PubMed, Embase, Wiley/Cochrane Library and ISI/Web of Science were searched from inception (by S.V. and J.K.) up to November 19, 2015. In addition, the clinical trial register was searched for ongoing studies [20]. The search strategy was developed together with a research librarian specialized in medical sciences, using the following terms (including synonyms and closely related words) as index terms or free-text words: ‘‘endometriosis’’ and ‘‘narrowband imaging’’ or ‘‘spectroscopy’’ or ‘‘3-dimensional imaging’’ or ‘‘fluorescence’’ or ‘‘dyes’’ or ‘‘indocyanine green’’ or ‘‘aminolevulinic acid’’ or ‘‘indigo carmine’’ and ‘‘laparoscopy’’ or ‘‘surgical procedures’’ or ‘‘peritoneal diseases’’ or ‘‘pelvis.’’ Duplicate articles were excluded. References lists of the retrieved publications were checked for relevant articles. The search strategies for all databases are described in detail in the Supplementary Information.

ELIGIBILITY CRITERIA All published randomized controlled trials, prospective cohort studies, retrospective cohort studies, case-control studies, case series and case reports were considered

32 for inclusion when the following criteria were met: reporting on the use of laparoscopic imaging techniques for the detection of endometriosis and reporting on the detection of endometriosis in humans. All other articles were excluded, as were articles published in languages other than English, Dutch, or German. Eligibility assessment of the retrieved articles was performed by 2 authors (M.L. and S.V.) independently (unblinded). In cases of disagreement regarding inclusion or exclusion of an article, the 2 authors discussed the article to establish a consensus. Figure 1 shows a flow diagram of the systematic literature search.

DATA PRESENTATION Data extraction was performed by 2 authors independently (M.L. and S.V.) and 2 included items about general study characteristics (design and period of the study, study population, and number of participants) and reported outcomes (sensitivity and specificity). Sensitivity represents the percentage of lesions identified as endometriosis during laparoscopy out of the total number of histopathologically confirmed endometriotic lesions. Specificity was defined as the percentage of tissue specimens identified on laparoscopy as healthy peritoneum out of the total number of histopathologically confirmed healthy biopsy specimens.

The quality of the primary diagnostic accuracy studies was assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool, through which risks for bias can be classified into 4 key domains: selection of participants, index (diagnostic) test, reference standard, and flow and timing of the study [21]. Along with the risk of bias assessment, the outcome of the domain on the research question was assessed as high or low applicability.

33 Chapter 2

FIGURE 1 - Flow diagram of inclusion of articles (version 2.0)

RESULTS

LITERATURE IDENTIFICATION Our literature search identified a total of 1971 reported patient records. The process of inclusion is shown in Figure 1. No additional records were identified by checking records reference lists. After removal of duplicates, 1347 records were screened to assess eligibility criteria for inclusion. A total of 65 articles were eventually selected for full-text assessment. Of these, 56 articles were excluded for the following reasons: study did not report on peritoneal endometriosis detection (n = 17); study design other than mentioned in eligibility criteria (n = 17); ex vivo, in vitro, or animal study (n = 14); study did not report on imaging techniques (n = 6); and article in a language other than English, Dutch, or German (n = 1, in Bulgarian). One study was excluded because it reported on the same patient population as a previous study and did not report on the intraoperative detection of endometriosis [22]. Eventually, 9 studies were included in this systematic review, reporting on a total of 432 women. Characteristics of the 9

34 studies are summarized in Table 1. Seven prospective cohort studies [24–30], 1 pilot study [23], and 1 randomized controlled trial [31] were identified with publication dates ranging from 1998 to 2015.

QUALITY ASSESSMENT The risk for bias was assessed according to the QUADAS-2 tool in 4 domains. Three studies scored low risk for bias in all 4 domains [25,28,31], and the other 6 studies scored high risk for bias in 1 or more domains. QUADAS-2 results are presented in Table 2.

REPORTED INTERVENTION 2 Four studies reported on the use of 5-ALA [23–26], 3 studies reported on AFI [27–29] and 2 studies reported on NBI [30,31]. Indications for endometriosis surgery were based on clinical suspicion of endometriosis in all studies. Five studies specifically reported pelvic pain as a clinical parameter [27,29–32]. Three studies also included patients with previously diagnosed endometriosis during previous laparoscopic inspection of the abdomen [23,25,27].

SURGICAL INTERVENTION Four prospective cohort studies reporting on 5-ALA and AFI used a similar methodology [25,26,28,29]. At first, the peritoneum was inspected with conventional laparoscopic WL imaging. Lesions suspicious for endometriosis by morphology were identified and systematically documented. Next, the peritoneum was inspected with the 5-ALA or AFI imaging technique. In the AFI studies [28,29], areas of reduced fluorescence were identified and documented, whereas in the 5-ALA studies [25,26], areas of fluorescence were identified. After identification and documentation, biopsy specimens of suspected lesions and altered fluorescent lesions were obtained to assess sensitivity. To assess specificity, control biopsy specimens of healthy- appearing peritoneum were obtained. Barrueto et al [31] conducted a randomized controlled trial including 150 patients. Patients were randomized at a 3:1 ratio between WL followed by NBI and WL alone. All lesions identified were documented and biopsied (n = 453). No biopsy specimens of healthy peritoneum were obtained. The Karl Storz D-LIGHT system (Karl Storz, Tuttingen, Germany) was used for 5-ALA and AFI studies, and the Olympus EXERA II system (Olympus, Tokyo, Japan) was used for NBI studies.

SENSITIVITY AND SPECIFICITY Five of the 9 studies reported sensitivity and specificity rates for detecting peritoneal endometriosis [25,26,28,29,31]. The results are presented in Table 3.

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5-ALA Two studies reported sensitivity rates for 5-ALA of 100% and 91%, compared with 69% and 62% respectively, for conventional WL [25,26]. Specificity rates were 75% to 78% for 5-ALA and 65% to 70% for WL.

AFI Sensitivity rates for AFI were 92% and 100%, compared with 65% and 48% respectively, for WL. Specificity for AFI was 84% to 88%, compared with 68% to 97% for WL.

NBI Barrueto et al [31] found a sensitivity of 100% for NBI, compared with 79% for WL (p < .001). They also scored the intraoperative clinical impression of 318 lesions and reported the lesions as either endometriosis or not endometriosis/indefinite endometriosis. They analyzed the sensitivity and specificity for their clinical impression of NBI and WL and found that sensitivity in detecting endometriosis was 84% for NBI and 71% for WL, whereas specificity decreased from 36% for WL to 24% for NBI. Moreover, all studies reported that the imaging techniques identified endometriotic lesions that were not detected with conventional WL.

SAFETY No adverse effects or complications related to the imaging techniques were reported in any of the 9 studies.

36

proven Reference standard Low Low Low Positive predictive

= System Storz D-light Storz D-light Storz D-light Storz D-light Storz D-light Storz D-light Storz D-light Olympus Exera II Olympus Exera II Hist = histologically Diagnostic test High High Low =pelvic pain; PPV Outcome Extra lesions Extra lesions Sens/spec Sens/spec Extra lesions Sens/spec Sens/spec PPV Sens/spec

endometriosis; 2 of Concerns regarding applicability Patient selection Low Low Low Indication Hist/Clin Clin Hist/Clin Clin Hist/PP Clin Clin/PP Clin/PP Clin/PP/ Infertility suspicion prospective cohort; PP

= Flow and Flow timing Low Low Low Clin = clinical Age, y 32.5 (26-41)* 32.5 [±4.3]† NA 30.8 [±5.4]† NA 33.2 [±5.4]† (33-38)* 36 (18-44)* 33.2 [±7.4]† Reference standard High High Low imaging; narrow-bandimaging; PCH Number of patients 16 15 37 24 25 83 45 20 167

= Diagnostic test Low Low Low Study design Pilot PCH PCH PCH PCH PCH PCH PCH RCT AFI = autofluorescence not available; NBI Risk for bias Patient selection Low Low Low

= Technique 5-ALA 5-ALA 5-ALA 5-ALA AFI AFI AFI NBI NBI fluorescence; Year 1998 2000 2000 Year 1998 2000 2000 2004 2004 2006 2007 2008 2015 acid-induced et al. [24]

Study characteristics QUADAS-2 risk bias of assessment et al. [23] et al. [25]

Author Malik et al. [23] Hillemans et al. [24] Malik et al. [25] Buchweitz et al. [26] Demco [27] Buchweitz et al. [28] Kupker et al. [29] Barrueto and Audin [30] Barrueto et al. [31] Author Malik Hillemans Malik Table 1 - Table 5-ALA = 5-aminolevulinic endometriosis during previouslaparoscopy; NA value; Sens = sensitivity; Spec = specificity; RCT = randomized controlled trial Median (range) * † Mean ± standard deviation 2 - Table

37 Chapter 2

available; Specificity IT, % 75% 78% 84% 88% NA 24%** Reference standard Low Low Low Low Low Low NA = not

imaging;

Sensitivity IT, % 100% 91% 92% 100% 100%*^ 84%** Diagnostic test Low High Low Low Low Low NBI = narrow-band

Specificity WL, % 70% 65% 68% 97% NA 36%** Concerns regarding applicability Patient selection Low Low Low Low Low Low technique; Flow and Flow timing Low Low Low Low High Low Sensitivity WL, % 69% 62% 65% 48% 79%*^ 71%** IT = imaging

Reference standard High High Low High Low Low imaging;

Healthy control control Healthy n biopsies, 12 36 38 15 0* 60** Diagnostic test Low Low Low Low Low Low AFI = autofluorescence No suspected lesions, n 112 37 160 112 453* 258**

Patient selection Low Low Low High Low Low Risk for bias fluorescence; Year 2004 2004 2006 2007 2008 2015 Technique 5-ALA 5-ALA AFI AFI NBI induced

Year 2000 2004 2006 2007 2015 acid et al. [26] et al. [28] et al. [26] et al. [28]

and Audin [30]and et al. [31] et al. [31]

QUADAS-2 risk bias of assessment (continued) [27] et al. [29] et al [29]

- Diagnostic properties white of light and imaging techniques et al. [25]

Author Buchweitz Demco Buchweitz Kupker Barrueto Barrueto Author Malik Buchweitz Buchweitz Kupker Barrueto Table 2 - Table Table 3 5-ALA = 5-aminolevulinic WL = white light ^ = p < .01 * Number lesions, of regardless clinical of impression **Clinical impression endometriotic of lesion during surgery

38 DISCUSSION

MAIN FINDINGS Based on our systematic review of 9 studies including 432 patients, enhanced imaging during laparoscopy has the potential to detect endometriotic lesions with better sensitivity then and comparable specificity to conventional WL imaging. Long- term clinical outcomes of the use of enhanced intraoperative imaging in laparoscopic treatment of endometriotic lesions have not been reported to date.

STRENGTHS AND LIMITATIONS Enhanced imaging for endometriosis is a relatively new focus of research. This 2 systematic review presents the current data on laparoscopic enhanced imaging techniques and their added value for intraoperative detection of peritoneal endometriosis. It underscores the importance of quality assessment according to the QUADAS-2 tool and suggests a standard approach to testing enhanced imaging in clinical application.

Although it is preferable to base conclusions of systematic reviews on the results of randomized controlled trials, in this field of relatively novel clinical research, only 1 such trial was available. In the absence of more randomized controlled trials, observational studies were included in this review, even though such studies represent a lower level of evidence. Clear inclusion criteria were used to select the reports for this study; nevertheless, the quality of this systematic review was restricted by the small sample sizes of the included trials and the lack of definitions of primary outcomes. Owing to the different methodologies used in the various studies, direct comparisons of imaging modalities were impossible and thus no firm conclusions can be drawn. Moreover, the risk of bias was frequently found in the reference standard domain, because the pathologist often was not blinded to the intraoperative results when evaluating the biopsy specimens.

INTERPRETATION OF THE EVIDENCE This systematic review shows that data evaluating the diagnostic accuracy of the enhanced imaging techniques is scarce and subject to limitations and biases. Consequently, no firm conclusions regarding the diagnostic accuracy of the various techniques can be drawn based on this review. Initial data suggest that there may be benefits from enhanced visualization that warrant further well-conducted clinical studies evaluating clinical outcomes. The methodology differed between the randomized controlled trial evaluating NBI [31] and the prospective cohort studies reporting on AFI and 5-ALA [25,26,28,29]. For example, Barrueto et al [31] biopsied every lesion regardless of its morphological appearance but obtained no control biopsy specimens of healthy appearing peritoneum, resulting in falsely low specificity rates. In addition, previous studies have reported high rates of healthy-appearing tissue to

39 Chapter 2 be endometriosis [33]. Therefore, Barrueto et al’s reported sensitivity rate of 100% could be biased by the absence of negative control biopsy specimens and thus no firm conclusions can be drawn regarding the diagnostic accuracy of NBI.

The prospective cohort studies reporting on AFI and 5-ALA did obtain negative control biopsy specimens of healthy peritoneum, thus providing more accurate sensitivity and specificity rates. Nonetheless, their methodology is limited owing to their nonrandomized design. Moreover, all authors inspected the peritoneum with the imaging modality after inspection with conventional WL imaging. In this way, the surgeon was provided with the locations of some lesions at the second round of inspection with the imaging modality, leading to reporting bias. This could have resulted in increased sensitivity rates for the imaging modalities. Nonetheless, and more importantly, the authors of all studies concluded that use of the imaging modalities identified additional lesions that would not have been detected using conventional WL imaging only.

A pitfall, especially with the methodology reported by Barrueto et al [31], is the low specificity. This can result in unnecessary resection of healthy tissue, producing postoperative neuropathic pain and adhesion formation [34].

The selection of patients may also have been subject to bias. Even though patients were enrolled consecutively and matching of cases and controls was avoided in most studies, only patients with a clinically strong suspicion of endometriosis and those with previously diagnosed endometriosis were included in all trials. This approach resulted in a study population with a high pretest probability of having endometriosis. When the likelihood of the presence of endometriosis is low, the attributive value of enhanced imaging is unclear [9]. Thus, the diagnostic properties that have been assessed by this review do not apply for this latter population. Nonetheless, the use of intraoperative imaging in this group of patients merits investigation in future studies.

A timeline in the application of techniques is noticeable. 5-ALA and AFI are reported mostly between 1998 and 2007, whereas NBI is reported in more recent publications, since 2008. Why no studies on the use of 5-ALA and AFI in endometriosis surgery have been reported after the study by Kupker et al [29] in 2007 is unclear, especially because the AFI technique has evolved since then, with the addition of a filter on the laparoscope camera that passes only green light (530 nm). This advance provides enhanced normal vs affected tissue contrast and is widely used in pulmonology and gastroenterology [18,35]. NIR-ICG is a more recently described technique; however, no prospective trials have been published to date. In the 1 published case report describing the use of ICG for endometriosis, Levy et al. reported finding lesions that were missed by conventional WL imaging. Our search of the clinical trial register

40 for ongoing studies found 1 study evaluating the diagnostic properties of ICG in 20 patients (NCT02038985) [20].

It is hypothesized that more complete resection of endometriosis could result in better long-term clinical outcomes, such as a prolonged pain-free interval, fewer reoperations and improved quality of life. Evidence of such improved outcomes is lacking and none of the included studies evaluated the clinical impact of the increased sensitivity of imaging techniques. Gallicchio et al [22], who published results from the same study population as Barrueto et al [31], found no significant differences in pain scores and quality of life at 3 and 6 months after the operation. However, recurrences and reoperations are usually seen later during follow-up [3]. 2

RECOMMENDATIONS This review shows that enhanced imaging modalities have the potential to improve the detection rate of endometriosis; however, to date, the data are limited mostly to cohort studies. Further research should focus on long-term clinical outcomes, such as pain-free interval, recurrence of symptoms, rate of reoperation, health care costs and quality of life, in a randomized setting. The effect of these imaging techniques on fertility needs to be assessed as well. Our study group has initiated a pilot trial (NTR5614) comparing conventional WL imaging with 3-dimensional imaging, NBI and NIR-ICG to directly evaluate the diagnostic properties of the different imaging techniques. The technique with best diagnostic accuracy will be further evaluated in a randomized clinical trial. In this trial, follow-up will be up to 2 years, and pain-free interval and quality of life will be evaluated.

CONCLUSION

Three intraoperative imaging techniques (5-ALA, AFI, and NBI) show promising results for detection of peritoneal endometriosis. However, the published studies of these techniques are at high risk for bias and lack data on long-term clinical outcomes in relation to the imaging technique used intraoperatively. Future studies should focus on long-term clinical outcomes, including quality of life, recurrence of symptoms, reoperation, and overall costs.

41 Chapter 2

REFERENCES

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42 21. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-536. 22. Gallicchio L, Helzlsouer KJ, Audlin KM, et al. Change in Pain and Quality of Life Among Women Enrolled in a Trial Examining the Use of Narrow Band Imaging During Laparoscopic Surgery for Suspected Endometriosis. J Minim Invasive Gynecol. 2015;22:1208-1214. 23. Malik E, Meyhofer-Malik A, Trutenau D, Diddens H, Kupker W, Diedrich K. Photodynamic diagnosis of endometriosis using 5-aminolevulinic acid - A pilot study. Geburtsh Frauenheilk. 1998;58:420-425. 24. Hillemanns P, Weingandt H, Stepp H, Baumgartner R, Xiang W, Korell M. Assessment of 5-aminolevulinic acid-induced porphyrin fluorescence in patients with peritoneal endometriosis. Am J Obstet Gynecol. 2000;183:52-57. 25. Malik E, Berg C, Meyhofer-Malik A, Buchweitz O, Moubayed P, Diedrich K. Fluorescence diagnosis of endometriosis using 5-aminolevulinic acid. Surg Endosc-Ultras. 2000;14:452-455. 2 26. Buchweitz O, Wulfing P, Staebler A, Kiesel L. Detection of nonpigmented endometriotic lesions with 5-aminolevulinic acid-induced fluorescence. J Am Assoc Gynecol Laparosc. 2004;11:505- 510. 27. Demco L. Laparoscopic spectral analysis of endometriosis. J Am Assoc Gynecol Laparosc. 2004;11:219-222 28. Buchweitz O, Staebler A, Tio J, Kiesel L. Detection of peritoneal endometriotic lesions by autofluorescence laparoscopy. Am J Obstet Gynecol. 2006;195:949-954. 29. Kupker W, Klenske J, Kornovski J. Autofluorescence and endometriosis: optical trap or new hope in diagnosis of endometriosis? Akush Ginekol (Sofiia). 2013;52:18–21. 30. Barrueto FF, Audlin KM. The use of narrowband imaging for identification of endometriosis. J Minim Invasive Gynecol. 2008;15:636-639. 31. Barrueto FF, Audlin KM, Gallicchio L, et al. Sensitivity of Narrow Band Imaging Compared With White Light Imaging for the Detection of Endometriosis. J Minim Invasive Gynecol. 2015;22:846- 852. 32. Levey KA. Use of fluorescence imaging technology to identify peritoneal endometriosis: a case report of new technology. Surg Laparosc Endosc Percutan Tech. 2014;24:e63-65. 33. Albee RB, Jr., Sinervo K, Fisher DT. Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis. J Minim Invasive Gynecol. 2008;15:32-37. 34. Davey AK, Maher PJ. Surgical adhesions: a timely update, a great challenge for the future. J Minim Invasive Gynecol. 2007;14:15-22. 35. Zaric B, Stojsic V, Sarcev T, et al. Advanced bronchoscopic techniques in diagnosis and staging of lung cancer. J Thorac Dis. 2013;5:S359-37

43 Chapter 2

SUPPLEMENTARY INFORMATION

Search strategy for PubMed (19 November 2015) [Mesh] = Medical subject headings [tiab] = words in title OR abstract

Search Query Items found #4 #1 AND #2 AND #3 503 #3 “Laparoscopy”[Mesh] OR laparoscop*[tiab] OR peritoneoscop*[tiab] OR 3,978,898 celioscop*[tiab] OR “Surgical Procedures, Operative”[Mesh] OR “surgery” [Subheading] OR surgery[tiab] OR surgeries[tiab] OR surgical*[tiab] OR operation*[tiab] OR operative*[tiab] OR resecti*[tiab] OR “Peritoneum”[Mesh] OR “Peritoneal Diseases”[Mesh] OR peritone*[tiab] OR mesenteri*[tiab] OR douglas pouch*[tiab] OR “Pelvis”[Mesh] OR pelvis[tiab] OR pelvic[tiab] #2 “Narrow Band Imaging”[Mesh] OR “Spectrometry, 969,830 Fluorescence”[Mesh] OR “Fluorescent Dyes”[Mesh] OR “Fluorescein Angiography”[Mesh] OR “Indigo Carmine”[Mesh] OR “Indocyanine Green”[Mesh] OR “Aminolevulinic Acid”[Mesh] OR “Imaging, Three- Dimensional”[Mesh:NoExp] OR narrowband imag*[tiab] OR narrow band imag*[tiab] OR nbi[tiab] OR nbis[tiab] OR spectrometr*[tiab] OR spectroscop*[tiab] OR fluoresce*[tiab] OR autofluoresce*[tiab] OR fluorochrom*[tiab] OR aminolevulin*[tiab] OR aminolaevulin*[tiab] OR levulan*[tiab] OR 5 ala*[tiab] OR 5ala*[tiab] OR photodynamic diagnos*[tiab] OR image guided surg*[tiab] OR chromoendoscop*[tiab] OR (“3 d”[tiab] OR 3d[tiab] OR 3dus[tiab] OR “3 dus”[tiab] OR 3dimension*[tiab] OR ((three[tiab] OR 3[tiab]) AND dimension*[tiab]) AND (image[tiab] OR images[tiab] OR imaging*[tiab])) OR “Spectroscopy, Near-Infrared”[Mesh] OR near infrared[tiab] #1 “Endometriosis”[Mesh] OR endometri*[tiab] 78,400

44 Search strategy for Embase.com (19 November 2015) /exp = EMtree keyword with explosion :ab,ti = words in title OR abstract NEXT/x = words in that order next to each other, x places apart NEAR/x = words in any order, x places apart

Search Query Items found #4 #1 AND #2 AND #3 1,048 #3 ‘laparoscopy’/exp OR ‘surgery’/de OR ‘abdominal surgery’/exp OR 3,062,112 ‘minimally invasive surgery’/exp OR ‘pelvis surgery’/exp OR ‘laser surgery’/exp OR ‘surgical technology’/exp OR ‘peritoneum’/exp 2 OR ‘peritoneal disease’/exp OR ‘pelvis’/exp OR laparoscop*:ab,ti OR peritoneoscop*:ab,ti OR celioscop*:ab,ti OR surgery:ab,ti OR surgeries:ab,ti OR surgical*:ab,ti OR operation*:ab,ti OR operative*:ab,ti OR resecti*:ab,ti OR peritone*:ab,ti OR mesenteri*:ab,ti OR (douglas NEXT/1 pouch*):ab,ti OR pelvis:ab,ti OR pelvic:ab,ti #2 ‘narrow band imaging’/exp OR ‘spectrofluorometry’/exp OR ‘fluorescent 1,118,027 dye’/exp OR ‘fluorescence angiography’/exp OR ‘indigo carmine’/exp OR ‘indocyanine green’/exp OR ‘indocyanine green angiography’/exp OR ‘aminolevulinic acid’/exp OR ‘three dimensional imaging’/exp OR ‘near infrared spectroscopy’/exp OR ‘near infrared reflectance spectroscopy’/ exp OR (narrowband NEAR/3 imag*):ab,ti OR (‘narrow band’ NEAR/3 imag*):ab,ti OR nbi:ab,ti OR nbis:ab,ti OR spectrometr*:ab,ti OR spectroscop*:ab,ti OR fluoresce*:ab,ti OR autofluoresce*:ab,ti OR fluorochrom*:ab,ti OR aminolevulin*:ab,ti OR aminolaevulin*:ab,ti OR levulan*:ab,ti OR (5 NEXT/1 ala*):ab,ti OR 5ala*:ab,ti OR (photodynamic NEAR/3 diagnos*):ab,ti OR (‘image guided’ NEAR/3 surg*):ab,ti OR chromoendoscop*:ab,ti OR (‘3 d’:ab,ti OR 3d:ab,ti OR 3dus:ab,ti OR ‘3 dus’:ab,ti OR 3dimension*:ab,ti AND (image:ab,ti OR images:ab,ti OR imaging*:ab,ti)) OR (three:ab,ti OR 3:ab,ti AND dimension*:ab,ti AND (image:ab,ti OR images:ab,ti OR imaging*:ab,ti)) OR ‘near infrared’:ab,ti #1 ‘endometriosis’/exp OR endometri*:ab,ti 103,358

45 Chapter 2

Search strategy for Wiley/Cochrane Library (19 November 2015) ti,ab,kw = words in title, abstract or keyword

Search Query Items found (CENTRAL) #1 (laparoscop* or peritoneoscop* or celioscop* or surgery or surgeries 11 or surgical* or operation* or operative* or resecti* or peritone* or mesenteri* or (douglas and pouch*) or pelvis or pelvic) and ((narrowband and imag*) or (“narrow band” and imag*) or nbi or nbis or spectrometr* or spectroscop* or fluoresce* or autofluoresce* or fluorochrom* or aminolevulin* or aminolaevulin* or levulan* or “5 ala” or “5 alas” or 5ala* or (photodynamic and diagnos*) or (“image guided” and surg*) or chromoendoscop* or ((“3 d” or 3d or 3dus or “3 dus” or 3dimension*) and (image or images or imaging*)) or ((three or 3) and dimension* and (image or images or imaging*)) or “near infrared”) and endometri*:ti,ab,kw (Word variations have been searched)

Search strategy for ISI/Web of Science (19 November 2015)

Search Query Items found #1 TOPIC: (((laparoscop* OR peritoneoscop* OR celioscop* OR surgery 409 OR surgeries OR surgical* OR operation* OR operative* OR resecti* OR peritone* OR mesenteri* OR (douglas AND pouch*) OR pelvis OR pelvic) AND ((narrowband AND imag*) OR (“narrow band” AND imag*) OR nbi OR nbis OR spectrometr* OR spectroscop* OR fluoresce* OR autofluoresce* OR fluorochrom* OR aminolevulin* OR aminolaevulin* OR levulan* OR “5 ala” OR “5 alas” OR 5ala* OR (photodynamic AND diagnos*) OR (“image guided” AND surg*) OR chromoendoscop* OR ((“3 d” OR 3d OR 3dus OR “3 dus” OR 3dimension*) AND (image OR images OR imaging*)) OR ((three OR 3) AND dimension* AND (image OR images OR imaging*)) OR “near infrared”) AND endometri*)) Indexes=SCI-EXPANDED, SSCI, A&HCI Timespan=All years

46 2

47

CHAPTER 3

Comparison of enhanced laparoscopic imaging techniques in endometriosis surgery: a diagnostic accuracy study

Lier, M.C.I. Vlek, S.L. Ankersmit, M. van de Ven, P.M. Dekker, J.J.M.L. Bleeker, M.C.G. Mijatovic, V. Tuynman, J.B.

Surg Endosc. 2020;34:96-104 Chapter 3

ABSTRACT

BACKGROUND For surgical endometriosis, treatment key is to properly identify the peritoneal lesions. The aim of this clinical study was to investigate if advanced imaging improves the detection rate by comparing narrow-band imaging (NBI), near-infrared imaging with indocyanine green (NIR-ICG), or three-dimensional white-light imaging (3D), to conventional two-dimensional white-light imaging (2D) for the detection of peritoneal endometriotic lesions.

METHODS This study was a prospective, single-center, randomized within-subject, clinical trial. The trial was conducted at Amsterdam UMC—Location VUmc, a tertiary referral hospital for endometriosis. 20 patients with ASRM stage III–IV endometriosis, scheduled for elective laparoscopic treatment of their endometriosis, were included. During laparoscopy, the pelvic region was systematically inspected with conventional 2D white-light imaging followed by inspection with NBI, NIR-ICG and 3D imaging in a randomized order. Suspected endometriotic lesions and control biopsies of presumably healthy peritoneum were taken for histological examination. The pathologist was blinded for the method of laparoscopic detection. Sensitivity and specificity rates of the enhanced imaging techniques were analyzed. McNemar’s test was used to compare sensitivity to 2D white-light imaging and Method of Tango to assess non- inferiority of specificity.

RESULTS In total, 180 biopsies were taken (117 biopsies from lesions suspected for endometriosis; 63 control biopsies). 3D showed a significantly improved sensitivity rate (83.5% vs. 75.8%, p = 0.016) and a non-inferior specificity rate (82.4% vs. 84.7%, p = 0.009) when compared to 2D white-light imaging. The single use of NBI or NIR-ICG showed no improvement in the detection of endometriosis. Combining the results of 3D and NBI resulted in a sensitivity rate of 91.2% (p < 0.001).

CONCLUSION Enhanced laparoscopic imaging with 3D white light, combined with NBI, improves the detection rate of peritoneal endometriosis when compared to conventional 2D white-light imaging. The use of these imaging techniques enables a more complete laparoscopic resection of endometriosis.

50 INTRODUCTION

Endometriosis, characterized by endometrial deposits in the peritoneal cavity, is a benign but chronic and potentially harmful disorder associated with pelvic pain complaints, subfertility and/or pelvic organ dysfunction [1]. Although endometriosis can be suspected on presenting symptoms, physical examination and imaging [e.g., transvaginal ultrasound (TVU) and magnetic resonance imaging (MRI)], laparoscopic identification and histological verification of endometriotic tissue remain the gold standard for the final diagnosis of the disease [2]. Treatment of symptomatic endometriosis, especially when not responding to hormonal treatment, consists of laparoscopic excision or ablation of endometriotic tissue [2]. However, the identification of endometriotic tissue during laparoscopy is not always clear which may partly contribute to the high rates of recurrence reported after surgical treatment (40–50% at 5 years) [3]. The polymorphic appearance of endometriotic 3 lesions is supposed to be the origin of this impaired visual diagnosis during laparoscopy, especially non-pigmented endometriotic lesions which are hard to distinguish from healthy peritoneal tissue [4–6]. Previous studies reported a positive predictive value of 2D white- light laparoscopy of only 66% [7]. Therefore, complete resection of endometriosis is difficult and reoperation, due to symptomatic recurrence, occurs in more than 50% of the patients [8]. The high costs of re-operation and the associated morbidity emphasize the importance of a more complete resection during primary surgery.

Enhanced laparoscopic imaging techniques, already frequently used in other fields of surgery [9–12], are promising additives to the intra-operative detection of endometriosis [13]. These techniques visualize differences in (neo)vascularization and epithelial thickness, possibly enabling an improved detection of endometriosis. Previous studies showed that with the use of 5-aminolevulinic acid-induced fluorescence (5-ALA) [14– 16], autofluorescence imaging (AFI) [17–19] and narrow-band imaging (NBI) [20, 21], endometriotic lesions were detected with a better sensitivity and equal specificity compared to 2D white-light imaging. Moreover, with these techniques additional endometriotic lesions were found that were not visualized with 2D white-light imaging only. The 5-ALA technique was, however, difficult to implement due to high costs and patient side effects, such as postoperative photosensitivity [14–16]. NBI has shown to be a more feasible technique available in most laparoscopic platforms and without any side effects. The effectiveness for the detection of peritoneal endometriosis of more recently introduced laparoscopic imaging techniques, such as near-infrared imaging with indocyanine green (NIR-ICG) [22, 23] or three-dimensional laparoscopy (3D), has not yet been investigated.

To directly compare these different enhanced laparoscopic imaging techniques, a clinical trial was conducted. We aimed to investigate which enhanced laparoscopic imaging technique is the most accurate for the detection of peritoneal endometriotic lesions, with respect to the sensitivity and specificity of the investigated techniques and compared to 2D white-light imaging.

51 Chapter 3

METHODS

STUDY DESIGN This study was a prospective, single-center, randomized within-subject, clinical trial conducted at the Amsterdam UMC—Location VUmc (VUmc, Amsterdam, the Netherlands). The study was approved by the institutional review board of the VUmc (METC VUmc 2015.392) and was registered as the LITE study (Laparoscopic Imaging Techniques in Endometriosis therapy) in the Dutch Trial Register (NTR5614, 06 January 2016). All participants provided informed consent prior to participation.

PATIENTS Women with moderate to severe endometriosis (American Society for Reproductive Medicine (ASRM), stage III or IV), who had an indication for elective laparoscopic treatment were asked for participation and informed consent. Endometriosis had to be previously surgically confirmed or likely to be present based on TVU or MRI findings (including uni- or bilateral ovarian endometrioma). All eligible patients were approached during the study period. Women were included if they were aged over 18 years and were premenopausal. Excluded from participation were women who were legally or mentally incapable or unable to give informed consent; pregnant women; women who had an American Society of Anesthesiologists (ASA) score > 3; major open abdominal surgery in the past; a known malignancy; an iodine allergy or hypersensitivity reaction to prior usage of ICG; use of any medication with a known interaction with ICG; chronic kidney failure (eGFR < 55); or abnormal liver enzyme tests (ASAT, ALAT, AF, and yGT > 2 times the maximum normal value).

TECHNIQUES In this trial, the following laparoscopic imaging techniques were studied: narrow- band imaging (NBI), near-infrared imaging with indocyanine green (NIR-ICG) and threedimensional white-light imaging (3D). These techniques were compared to conventional two-dimensional high-definition white-light imaging (2D) using the laparoscopic system CLV-180 EVIS EXERA II platform (Olympus, Center Valley, USA) with an ENDOEYE FLEX 3D deflectable videoscope in the 2D viewing mode.

NARROW-BAND IMAGING (NBI) NBI was applied using the standard available settings from the laparoscopic system CLV-180 EVIS EXERA II platform (Olympus, Center Valley, USA) with an ENDOEYE FLEX 3D deflectable videoscope. In NBI imaging, two specific wavelengths of light are filtered that are strongly absorbed by hemoglobin. The shorter wavelength (415 nm) only penetrates the superficial layers of the mucosa and is absorbed by capillary vessels in the surface of the mucosa. The second wavelength (540 nm) penetrates deeper and is absorbed by blood vessels located deeper within the mucosal layer, allowing visualization of the vasculature of suspected endometriotic lesions.

52 NEAR-INFRARED IMAGING WITH INDOCYANINE GREEN (NIR-ICG) For the NIR-ICG procedure indocyanine green (ICG, ICGPULSION ®, PULSION Medical Systems AG, Munich, Germany) was intravenously applied through a peripheral infusion during surgery. ICG is a sterile water soluble tricarbocyanine dye with a peak spectral absorption in blood (plasma) at 800–810 nm (range: 750–950 nm). ICG powder was diluted with sterile water for injection to a final solution of 0.25 mg/mL. A bolus of 1 mL ICG solution was injected through a peripheral IV line at the start of the procedure. If visualization was inadequate an extra bolus of 1 mL was administered. ICG was administered directly under nearinfrared vision and after administration a time period of 5 min was used for the detection of lesions. The Olympus VISERA Pro (Olympus, Center Valley, USA) laparoscopic platform was used with a modified filter on the videoscope that excited near-infrared light (800 nm) and filtered nearinfrared reflection in the range of 700–900 nm, enabling visualization of the increased (neo) 3 vascularity of endometriotic lesions.

THREE-DIMENSIONAL WHITE-LIGHT IMAGING (3D) 3D imaging was applied using the laparoscopic system CLV-180 EVIS EXERA II platform (Olympus, Center Valley, USA) with an ENDOEYE FLEX 3D deflectable videoscope. The dual lens generated 3D images, projected on a 3D monitor. Lightweight polarized 3D eyewear integrated the images into 3D vision and enabled depth perception with accurate color reproduction.

SURGERY AND IMAGING Patients were placed in the supine position and received general anesthesia. After introduction of the videoscope through a 12-mm trocar, the abdominal cavity was inspected. Two additional 5-mm trocars were placed to facilitate exposure of the pelvic cavity. For a systematic approach and recording of the suspected lesions, the pelvic cavity was divided in seven regions: region I—left lateral pelvic wall and bladder peritoneum; region II—right lateral pelvic wall and bladder peritoneum; region III— peritoneal surface of the uterus; region IV—left lower region of the pelvis (including ovarian surface, round ligament, uterosacral ligament, and Douglas’ Pouch); region V— right lower region of the pelvis (including ovarian surface, round ligament, uterosacral ligament, and Douglas’ Pouch); region VI—left ovarian fossa and region VII—right ovarian fossa [Figure 1]. All regions were first inspected systematically with conventional 2D white-light imaging. Inspection was repeated with the other imaging techniques (NBI, NIR-ICG, 3D), applied in a randomized order, generated by online randomization tool Sealed Envelope Ltd. (London, United Kingdom). Visual diagnosis of endometriosis was confirmed according to previously described criteria [24, 25]. All inspections were performed by the same operating physician (VM). Suspected endometriotic lesions were identified, documented and numbered. After full surveillance with all imaging techniques and documentation, all suspected endometriotic lesions were excised. Biopsies of healthy appearing peritoneum were taken as negative controls.

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No biopsies were taken of regions with increased risk of iatrogenic damage, bleeding, or perforation, such as the intestines or lesions nearby large blood vessels.

The collected specimens were processed, hematoxylin and eosin (H&E) stained and assessed upon the presence of endometriosis (identification of endometriotic glands and/or endometrial stroma). Additional immunostaining for CD10 and estrogen receptors (ER) was applied if the presence or absence of endometriosis could not be confirmed based on the H&E staining only [26–28]. The pathologist was blinded for the method of detection (e.g., the used imaging technique) and for the clinical suspicion of endometriosis (e.g., specimens obtained from areas suspected or unsuspected (control) for endometriosis).

FIGURE 1 - Schematic image of pelvic region

54 OUTCOMES The primary objective was to evaluate the sensitivity and specificity rates of the imaging techniques in the detection of peritoneal endometriosis, when compared to 2D white-light imaging. Secondary outcomes were false-negative rate, false-positive rate and accuracy.

SAMPLE SIZE CALCULATION Sample size calculation for this study was based on the number of endometriotic lesions needed to achieve 80% power to detect an increase in sensitivity from 72% (for conventional 2D white light) to 85% (for enhanced imaging techniques) assuming 70% of the endometriotic lesions to be detected by all techniques. Sample size was based on a two-sided McNemar test. Power analysis performed in PASS revealed a required number of 81 pathologically confirmed endometriosis lesions. We expected to find a mean number of 5.5 endometriotic lesions per patient in our population as 3 previously described [29]. Therefore, the sample size was set at 20 patients.

STATISTICS After final pathologic results were confirmed, the outcomes were put in two-by-two contingency tables to calculate the primary outcomes: sensitivity [true positives/(true positives + false negatives)] and specificity [true negatives/(true negatives + false positives)] rates for each imaging technique. Also the false-negative rates [false negatives/ (true positives + false negatives)] and false-positive rates [false positives/(true negatives + false positives)] were calculated. Test accuracy was calculated for this specific set of biopsies [(true positives + true negatives)/total biopsies]. Area under the receiver operator characteristics (AUROC) was calculated for each imaging technique. Comparative testing was only performed for the primary outcomes (sensitivity and specificity). To compare sensitivity of the enhanced imaging techniques (3D, NBI, and NIR-ICG) to conventional 2D white-light imaging, McNemar’s test was used. Results were considered statistically significant with p < 0.05 for two-sided testing. Non-inferiority of specificity of enhanced imaging techniques was tested using the method of Tango [30] assuming the prespecified non-inferiority margin of 10%. For non-inferiority a one-sided p < 0.025 was considered significant. Additional analyses were performed where we took into account clustering of lesions within patients. Sensitivity was compared using Generalized Estimating Equations (GEE) with an exchangeable working correlation structure to account for within-patient correlation of test outcomes. To assess non-inferiority of specificity, a similar approach was used. From the GEE output, a p-value for non-inferiority was derived from the estimate of the difference in specificities and the reported standard error of this difference where we assumed that the estimated difference was normally distributed. Post hoc analyses were performed in which we evaluated the sensitivity and specificity for combining NBI and 3D where positivity was defined as being either positive on at least one (NBI and/or 3D) of these methods or positive on both (NBI and 3D) methods, respectively. Statistical analyses were performed with SPSS 22 (IBM, Chicago, USA) software. The non-inferiority tests assuming independence of observations were performed using Excel.

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RESULTS

INCLUSIONS Between February 2016 and May 2017, 20 participants were included in this trial. Baseline characteristics are shown in Table 1. In total, 180 biopsies were taken, of which 117 biopsies were taken from lesions suspected for endometriosis and 63 biopsies were taken from presumably healthy peritoneum (negative controls). The median number of endometriotic lesions per patient was 5.5 (IQR 5–7.5) with a median number of 3.5 control biopsies (IQR 2–4). After histological examination, endometriosis was confirmed in 91 biopsies, 85 biopsies were negative for endometriosis. Four biopsies were inconclusive, meaning that the presence or absence of endometriosis could not be confirmed after histological examination.

Table 1 - Baseline characteristics

Total (n=20) Age at surgery (yrs), Median (IQR) 34.5 (29.3 – 39.5) Race, n (%) Caucasian 17 (85%) BMI (kg/m2), n (%) <25 12 (60%) 25-30 8 (40%) Parity, Median (IQR) 0 (0 - 1) Active childwish, n (%) 7 (35%) Prior abdominal surgery, n (%) 8 (40%) Reported pre-operative complaints, n (%) Dysmenorrhea 19 (95%) Dyschezia 13 (65%) Dysuria 1 (5%) Dyspareunia 10 (50%) Use of pre-operative medication, n (%) Yes, oral contraceptives 8 (40%) Yes, GnRH agonist 3 (15%) No 9 (45%)

BMI = Body Mass Index; IQR = interquartile range; n = number; yrs = years

IMAGING TECHNIQUES Biopsies with inconclusive results were excluded when calculating and comparing the diagnostic properties of the imaging techniques. Table 2 displays the primary outcomes, sensitivity and specificity rates of the different imaging techniques. 3D white-light imaging showed a significantly improved sensitivity rate [83.5% vs. 75.8%, p = 0.016 (uncorrected)/p = 0.005 (multi-level)] and a non-inferior specificity rate [82.4% vs. 84.7%, p = 0.009 (uncorrected)/p = < 0.001 (multi-level)] when compared to 2D white-light imaging. The single use of NBI or NIR-ICG showed no improvement in the

56 detection of endometriosis. False-positive rates were 15.3%, 17.6%, 29.4%, and 11.0%; false-negative rates (i.e., miss rates) were 24.2%, 16.5%, 18.7%, and 63.9%; accuracy was 80.1%, 83.0%, 76.1%, and 58.5% for 2D white-light imaging, 3D white-light imaging, NBI, and NIR-ICG, respectively. Combining the results of 3D white-light imaging and NBI in a post hoc analysis resulted in a significantly improved sensitivity rate for the detection of endometriotic lesions [91.2% vs. 75.8, p < 0.001 (uncorrected)/p < 0.001 (multi-level)], however with a specificity rate inferior to 2D white-light imaging [0.6% vs. 75.8%, p = 0.90 (uncorrected)/p = 0.83 (multilevel)] [Table 3].

Table 2 - Sensitivity and specificity rates

Visual examination, Histological examination, endometriosis presence of endometriosis suspected based on; confirmed; 3 Yes No p-value (uncorrected/multi-level) 2D (WL) Yes 69 13 Sensitivity 75.8% - (n=176) No 22 72 Specificity 84.7% - FP-rate 15.3% FN-rate 24.2% Accuracy 80.1%

NBI Yes 74 25 Sensitivity 81.3% p=0.36/p=0.29 (n=176) No 17 60 Specificity 70.6% p=0.90/p=0.83 FP-rate 29.4% FN-rate 18.7% Accuracy 76.1%

NIR-ICG Yes 30 9 Sensitivity 36.1% p<0.001/p<0.001a (n=165) No 53 73 Specificity 89.0% p=0.002/p<0.001b FP-rate 11.0% FN-rate 63.9% Accuracy 58.5%

3D Yes 76 15 Sensitivity 83.5% p=0.016/p=0.005a (n=176) No 15 70 Specificity 82.4% p=0.009/p=<0.001b FP-rate 17.6% FN-rate 16.5% Accuracy 83.0%

2D = 2D imaging; 3D = 3D imaging; FN-rate = false-negative rate; FP-rate = false-positive rate; NBI = narrow-band imaging; NIR-ICG = near-infrared imaging with indocyanine green; n = number; WL = white-light imaging a p < 0.05 for the McNemar’s test for differences in sensitivity b p < 0.025 for establishing non-inferiority of specificity compared to WL

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Table 3 - Sensitivity and specificity rates for combination 3D and/or NBI

Visual examination, Histological examination, endometriosis suspected presence of endometriosis based on; confirmed; Yes No p-value (uncorrected/multi-level) 3D AND NBI Yes 67 15 Sensitivity 73.6% p=0.77/p=0.83 (n=176) No 24 70 Specificity 82.4% p=0.009/p<0.001a FP-rate 17.6% FN-rate 26.4% Accuracy 77.8%

3D AND/OR NBI Yes 83 25 Sensitivity 91.2% p<0.001/p<0.001b (n=176) No 8 60 Specificity 70.6% p=0.90/p=0.38 FP-rate 29.4% FN-rate 8.6% Accuracy 81.3%

3D AND NBI displays that endometriosis was suspected upon visual inspection of both 3D and NBI; 3D AND/OR NBI displays that endometriosis was suspected upon either 3D, NBI, or both techniques; 3D = 3D imaging; FN-rate = false-negative rate; FP-rate = false-positive rate; NBI = narrow-band imaging; n = number a p < 0.025 for establishing non-inferiority of specificity compared to WL b p < 0.05 for the McNemar’s test for differences in sensitivity

For all imaging techniques and the post hoc analysis for combining 3D and NBI, AUROC has been generated [Table 4] [Figure 2].

Table 4 - Area under the receiver operator characteristics

Imaging technique Area 2D (WL) .810 NBI .759 NIR-ICG .617 3D .828

Post hoc analysis Area NBI AND 3D .786 NBI AND/OR 3D .801

2D = 2D imaging; 3D = 3D imaging; NBI = narrow-band imaging; NIR-ICG = near-infrared imaging with indocyanine green; WL = white-light imaging

58 Figure 2 - AUROC curves

3

3D = 3D imaging; NBI = narrow-band imaging; ICG = near-infrared imaging with indocyanine green

Twenty-two biopsies were positive for endometriosis after histological examination, but were not visualized with 2D white-light imaging; of these biopsies, 12/22 were visualized with NBI, 4/22 with NIR-ICG, and 7/22 with 3D white-light imaging. 7/22 biopsies were not visualized with any of the enhanced imaging techniques or conventional 2D white-light imaging.

INTRA-OPERATIVE PARAMETERS Operating time was extended with a median of 30 min (30–37.5 min) due to the thorough inspection of the peritoneum with all the imaging techniques including the histological sampling. The median amount of blood loss was 50 mL (IQR: 27.5 mL–100 mL). No complications or serious adverse events were reported.

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DISCUSSION

This study was designed to investigate which enhanced laparoscopic imaging techniques would show increased sensitivity and non-inferior specificity for the detection of peritoneal endometriosis. The use of 3D white-light imaging significantly improved the sensitivity rates for the detection of endometriotic lesions when compared to conventional 2D white-light imaging and showed a comparable specificity rate. The combined use of NBI and 3D white-light imaging, both available on the standard laparoscopic platform, resulted in the highest sensitivity rate for the detection of peritoneal endometriotic lesions. The use of NBI and NIR-ICG alone showed to be of less value with decreased specificity and sensitivity rates, respectively.

These are novel findings with potential to improve surgical care for patients with endometriosis and were not reported in previous studies on the use of enhanced laparoscopic imaging techniques in endometriosis surgery. Additional analyses accounting for clustering of lesions within patients did not change our results and conclusions.

Previous studies in other fields of surgery showed that experienced surgeons’ skills improve with 3D vision compared to 2D vision [31,32]. It is hypothesized that a 3D view of endometriotic lesions may be advantageous for the identification of endometriosis detection, showing more clearly an altered peritoneal lining and thickening induced by endometriosis. Inflammation causes a slight swelling of the peritoneum which presumably is the base of this improved recognition by 3D view.

In our clinical study, a (indirect) combination of NBI and 3D white-light imaging resulted in a significantly improved sensitivity rate. The application and addition of NBI to 3D white-light imaging is useful since the visualization of micro-vascularization is enhanced, as is observed in endoscopy for adenomatous lesions [33]. In addition, since NBI is integrated in the standard imaging processor of 2D and 3D equipment, no additional material or handling is necessary to incorporate these imaging techniques together in daily practice. Previous studies investigating the use of NBI [20,21] also showed an increased sensitivity rate when NBI was added to 2D white-light imaging for the identification of peritoneal endometriosis. However, the use of NBI alone was not superior compared to the combined 2D/NBI modality and no control biopsies were taken to calculate specificity rates. The low specificity rate of NBI (with and without combined 3D view) of 71% may lead to an unjustified resection of presumed endometriotic lesions and a subsequent increased risk for surgical complications. However, since the excised endometriotic lesions are small and in need for small laser ablative therapy, with low associated morbidity, this might be of less clinical relevance. To increase specificity rates in the future, a learning phase with direct feedback of each

60 nodule after reviewing the pathology might increase the specificity without hampering sensitivity rates.

Two case reports have been published regarding the use of NIR-ICG [22,23]. In both studies, Firefly fluorescence detection systems (Intuitive Surgical Inc., Sunnyvale, USA) were used. The authors describe fluorescence has aided them in detection and resection of endometriosis. A recent cohort study was published, comparing NIR- ICG to 2D white-light imaging, revealing comparable sensitivity and specificity rates [34]. In our trial, however, a significantly decreased sensitivity rate of 36% compared to 2D white-light imaging was detected. Pathologic examination revealed that 43 out of 66 endometriotic lesions were not identified by fluorescent imaging. In our study, we administered the ICG directly under near-infrared vision, but up to 5 min was utilized to detect endometriotic lesions. Cosentino et al. (2018) administered ICG 3 5–30 min prior to inspection. Based on their results, we believe the use of NIR-ICG for detection of endometriosis could be further examined. However, most promising field of fluorescence-guided surgery will probably be the use of monoclonal endometriosis- specific antibodies coupled to a fluorescent marker. These potential promising new strategies deserves further research, as has been shown for cancer detection with CEA (bevacizumab) labeled to IRdye-800CW (a fluorescent agent, comparable to ICG) [35].

In this study, we decided not to investigate the 5-ALA technique [14–16]. Due to increased photosensitivity of the skin, patients are required to refrain from light for 24 h after ingestion of 5-ALA. We believe this is not patient friendly and not feasible for our patients whom are treated in day surgery. Secondly, the use of 5-ALA would not be cost effective.

Intra-operative identification of endometriosis is not only depending upon the ability to visualize lesions, but also upon the experience of the surgeon who performs the inspection. In this study, all procedures were performed by the same gynecologist (VM), an experienced endometriosis specialist. A potential weakness is the bias presented by the use of a single surgeon for all imaging modalities. Therefore, we have randomized the order in which imaging techniques were applied during laparoscopic inspection. Moreover, we have blinded the pathologist for the method of detection and clinical suspicion of endometriosis, in order to minimize bias and strengthen the results of this study. This trial was limited by the fact that the interrater variability was not assessed, neither was the learning curve. Although the surgeon had a large experience in detection of endometriosis with 2D white-light imaging, this was less for 3D white-light imaging, NBI and NIR-ICG. Potentially after a learning curve, even better performance could be present with these imaging techniques. Further validation of the different imaging techniques should be addressed in future studies.

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In this clinical trial, only patients with preoperatively established moderate to severe endometriosis (ASRM III–IV) were included, as we expected to encounter a sufficient amount of peritoneal disease in them. This study does not answer the question whether enhanced imaging techniques improve the detection of endometriosis in patients with limited peritoneal disease (ASRM I–II). In patients with limited peritoneal disease, an increased specificity (i.e., improved accuracy in showing the absence of disease) might be preferable, whereas in patients with high disease load (ASRM III–IV) improved sensitivity is preferable in order to achieve complete resection.

This study was designed as an explorative development study to identify which enhanced laparoscopic imaging technique has the best diagnostic accuracy for the detection of peritoneal endometriosis in terms of sensitivity (superior) and specificity (non-inferior). Based on the results of this trial, a further exploration of the use of NBI/3D white-light imaging is needed and will now be further evaluated in a large randomized clinical trial with clinical relevant endpoints according to the IDEAL framework with adequate power, quality control, and measures [36]. The clinical question is whether an improved detection of endometriosis with NBI/3D imaging also affects the long-term clinical outcomes after surgery, like reintervention rates, pain-free interval and quality of life.

CONCLUSIONS

Enhanced laparoscopic imaging with 3D white light, combined with NBI, improves the detection rate of peritoneal endometriosis when compared to conventional 2D white- light imaging. The use of these imaging techniques may potentially result in a more complete laparoscopic resection of endometriosis.

62 REFERENCES

1. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698-2704. 2. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400-412. 3. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441-461. 4. Jansen RP, Russell P. Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol. 1986;155:1154-1159. 5. Nisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59:681-684. 6. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817-821. 7. Marchino GL, Gennarelli G, Enria R, Bongioanni F, Lipari G, Massobrio M. Diagnosis of pelvic endometriosis with use of macroscopic versus histologic findings. Fertil Steril. 2005;84:12-15. 3 8. Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: How often do we need to re-operate? J Obstet Gynaecol. 2008;28:82-85. 9. Hewett DG, Kaltenbach T, Sano Y, et al. Validation of a simple classification system for endoscopic diagnosis of small colorectal polyps using narrow-band imaging. Gastroenterology. 2012;143:599-607.e1. 10. He Q, Wang Q, Wu Q, Feng J, Cao J, Chen BY. Value of autofluorescence imaging videobronchoscopy in detecting lung cancers and precancerous lesions: a review. Respir Care. 2013;58:2150-2159. 11. Wanders LK, East JE, Uitentuis SE, Leeflang MM, Dekker E. Diagnostic performance of narrowed spectrum endoscopy, autofluorescence imaging, and confocal laser endomicroscopy for optical diagnosis of colonic polyps: a meta-analysis. Lancet Oncol. 2013;14:1337-1347. 12. Eljamel S. 5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta- Analysis of the Literature. Int J Mol Sci. 2015;16:10443-10456. 13. Vlek SL, Lier MC, Ankersmit M, et al. Laparoscopic Imaging Techniques in Endometriosis Therapy: A Systematic Review. J Minim Invasive Gynecol. 2016;23:886-892. 14. Hillemanns P, Weingandt H, Stepp H, Baumgartner R, Xiang W, Korell M. Assessment of 5-aminolevulinic acid-induced porphyrin fluorescence in patients with peritoneal endometriosis. Am J Obstet Gynecol. 2000;183:52-57. 15. Malik E, Berg C, Meyhöfer-Malik A, Buchweitz O, Moubayed P, Diedrich K. Fluorescence diagnosis of endometriosis using 5-aminolevulinic acid. Surg Endosc. 2000;14:452-455. 16. Buchweitz O, Wülfing P, Staebler A, Kiesel L. Detection of nonpigmented endometriotic lesions with 5-aminolevulinic acid-induced fluorescence. J Am Assoc Gynecol Laparosc. 2004;11:505- 510. 17. Demco L. Laparoscopic spectral analysis of endometriosis. J Am Assoc Gynecol Laparosc. 2004;11:219-222. 18. Buchweitz O, Staebler A, Tio J, Kiesel L. Detection of peritoneal endometriotic lesions by autofluorescence laparoscopy. Am J Obstet Gynecol. 2006;195:949-954. 19. Kupker W, Klenske J, Kornovski J. [Autofluorescence and endometriosis optical trap or new hope in dianosis of endometriosis?]. Akush Ginekol (Sofiia). 2013;52:18-21 20. Barrueto FF, Audlin KM. The use of narrowband imaging for identification of endometriosis. J Minim Invasive Gynecol. 2008;15:636-639.

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21. Barrueto FF, Audlin KM, Gallicchio L, et al. Sensitivity of Narrow Band Imaging Compared With White Light Imaging for the Detection of Endometriosis. J Minim Invasive Gynecol. 2015;22:846- 852. 22. Levey KA. Use of fluorescence imaging technology to identify peritoneal endometriosis: a case report of new technology. Surg Laparosc Endosc Percutan Tech. 2014;24:e63-e65. 23. Guan X, Walsh T, Osial P, Xu D, Bridgett K. Robotic Single-Site Endometriosis Resection Using Firefly Technology. J Minim Invasive Gynecol. 2015;22:S118. 24. Martin DC, Hubert GD, Vander Zwaag R, el-Zeky FA. Laparoscopic appearances of peritoneal endometriosis. Fertil Steril. 1989;51:63-67. 25. Redwine DB. Is “microscopic” peritoneal endometriosis invisible? Fertil Steril. 1988;50:665-666. 26. Fujishita A, Nakane PK, Koji T, et al. Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study. Fertil Steril. 1997;67:856-864. 27. Groisman GM, Meir A. CD10 is helpful in detecting occult or inconspicuous endometrial stromal cells in cases of presumptive endometriosis. Arch Pathol Lab Med. 2003;127:1003-1006. 28. Potlog-Nahari C, Feldman AL, Stratton P, et al. CD10 immunohistochemical staining enhances the histological detection of endometriosis. Fertil Steril. 2004;82:86-92. 29. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89:1632-1636. 30. Tango T. Equivalence test and confidence interval for the difference in proportions for the paired-sample design. Stat Med. 1998;17:891-908. 31. Cicione A, Autorino R, Breda A, et al. Three-dimensional vs standard laparoscopy: comparative assessment using a validated program for laparoscopic urologic skills. Urology. 2013;82:1444- 1450. 32. Alaraimi B, El Bakbak W, Sarker S, et al. A randomized prospective study comparing acquisition of laparoscopic skills in three-dimensional (3D) vs. two-dimensional (2D) laparoscopy. World J Surg. 2014;38:2746-2752. 33. Ikematsu H, Matsuda T, Osera S, et al. Usefulness of narrow-band imaging with dual-focus magnification for differential diagnosis of small colorectal polyps. Surg Endosc. 2015;29:844- 850. 34. Cosentino F, Vizzielli G, Turco LC, et al. Near-Infrared Imaging with Indocyanine Green for Detection of Endometriosis Lesions (Gre-Endo Trial): A Pilot Study. J Minim Invasive Gynecol. 2018;25:1249-1254. 35. Harlaar NJ, Koller M, de Jongh SJ, et al. Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study. Lancet Gastroenterol Hepatol. 2016;1:283-290. 36. Hirst A, Philippou Y, Blazeby J, et al. No Surgical Innovation Without Evaluation: Evolution and Further Development of the IDEAL Framework and Recommendations. Ann Surg. 2019;269:211- 220.

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CHAPTER 4

Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial

Lier, M.C.I. Van der Houwen, L.E.E. Schreurs, A.M.F. van Wely, M. Hompes, P.G.A. Cantineau, A.E.P. Schats, R. Lambalk, C.B. Mijatovic, V.

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ABSTRACT

STUDY QUESTIONS The primary objective is to investigate if continuous use of oral contraceptives is non-inferior compared to longterm pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with moderate to severe endometriosis with regard to treatment efficacy. Secondary objectives concern treatment safety and cost-effectiveness.

WHAT IS KNOWN ALREADY Long-term pituitary desensitization with a GnRH agonist for 3–6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. However, discussion about this treatment strategy exists because of its uncomfortable side effects. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower (in)direct costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pretreatment strategies in women with endometriosis have not been directly compared.

STUDY DESIGN, SIZE, DURATION An open-label, parallel two-arm randomized controlled multicenter trial is planned, including patients with moderate to severe endometriosis. To demonstrate an absolute difference of 13% (delta of 10% with non- inferiority margin of 3%) with a power of 80%, 137 patients per group are sufficient. Taking into account a withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure), the sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, eligible patients will be randomly allocated to the intervention or reference group by using web based block randomization stratified per centre. Study inclusion is expected to be complete in 3–5 years.

PARTICIPANTS/MATERIALS, SETTING, METHODS The research population consists of patients with moderate to severe endometriosis (ASRM III/IV) who are scheduled for their first, second or third IVF/ICSI treatment attempt. Women aged over 41 years, younger than 18 years, with a known contraindication for the use of oral contraceptives and/or GnRH agonists or with severe male factor infertility will be excluded from participation. After informed consent patients are allocated to the intervention group (one-phase oral contraceptive continuously during three subsequent months) or the reference group (three Leuprorelin 3.75 mg i.m./s.c. depot injections during three subsequent months). Tibolon 2.5mg can be given daily as add-back therapy in the reference group. After 3 months of pre-treatment the IVF/ICSI stimulation phase will be started. The primary outcome is live birth rate after fresh embryo transfer. Secondary outcomes are cumulative live birth rate after one IVF/ICSI treatment cycle (including fresh and frozen embryo transfers up to 15 months after randomization), ongoing pregnancy rate and time to pregnancy. In addition, treatment outcome parameters,

68 adverse events, side-effects during the first 3 months, complications, recurrence of endometriosis (complaints), quality of life, patient preferences, safety and costs effectiveness will be reported. Measurements will be performed at baseline and at 3, 6, 9, 12 and 15 months after randomization.

STUDY FUNDING/COMPETING INTEREST(S) All authors have no conflict of interest related to this manuscript. The department of reproductive medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work.

TRIAL REGISTRATION NUMBER The trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl).

TRIAL REGISTRATION DATE 16 March 2017. 4

DATE OF FIRST PATIENT’S ENROLLMENT Enrollment is planned for November 2018.

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INTRODUCTION

Endometriosis is associated with subfertility in up to 50% of patients [1]. In patients with severe endometriosis, subfertility is presumed to be based on a distortion of the pelvic anatomy, a hostile peritoneal environment, a decreased oocyte quality, a diminished ovarian reserve (due to the presence of endometrioma or prior ovarian surgery) and/ or an impaired implantation due to an altered endometrial receptivity [2,3]. Especially in cases of tubal dysfunction, in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are stated as appropriate treatments for subfertility in endometriosis patients by the European Society of Human Reproduction and Embryology (ESHRE) guideline [4]. However, inferior success rates are especially described in patients with moderate to severe endometriosis (American Society for Reproductive Medicine (ASRM) Stage III and IV) and in patients with endometrioma(s) [5-8].

To improve pregnancy rates after IVF/ICSI, it is recommended to precede IVF/ICSI by long-term pituitary desensitization with a GnRH agonist for 3–6 months, since this is shown to improve clinical pregnancy rates (CPR) [9-17]. However, the mechanism responsible for this increase in clinical pregnancy rate is not yet clarified and more research is needed.

Furthermore, as both the Cochrane and ESHRE recommendations are based upon only three small randomized studies (N = 165) [12,15,17], executed in a different IVF/ICSI treatment era in which more aggressive stimulation was used and multiple embryos were transferred, debate about this treatment strategy exists. Additionally, different study-populations with varying degrees of endometriosis (ASRM Stage II–IV) were included in these trials [12,15,17], which could have influenced the results.

It is also postulated that the use of a long-term pituitary desensitization regime may lower ovarian response to ovarian stimulation, especially in poor responders [18]. In addition, uncomfortable side effects, such as vasomotor instability, are often reported by patients. These side effects might result in a restrained attitude in prescribing this treatment strategy for a longer period of time, although add-back therapy is available to diminish these vasomotor side-effects [19,20]. On the other hand, patients who used long-term GnRH agonists prior to IVF reported to be motivated to use this treatment strategy again, despite side-effects, in a next IVF/ICSI attempt [21].

Alternatively, the effect of continued use of oral contraceptives (OCs) for 6–8 weeks prior to IVF/ICSI has been investigated [22]. Non-randomized data show that this treatment is favourable in patients with severe endometriosis undergoing IVF/ICSI, as clinical pregnancy rates were higher compared to endometriosis patients treated without OCs and comparable to that of control patients without endometriosis [22]. However, a randomized comparison between continuous use of OCs and longterm

70 pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with endometriosis has not yet been made.

The daily uncomfortable vasomotor side-effects that are associated with a GnRH agonist treatment without add-back therapy, are negatively associated with work- ability and increase the risk of sickness absence [23-26]. It is currently unknown if this can be positively influenced by using add-back therapy.

Although the tolerability of OC is higher compared to GnRH agonists (with or without add-back therapy) [27],its use is known to be often associated with migraine, weight gain, depression and with a higher risk on venous and arterial thromboembolism [28,29]. By using OC continuously, a reduction in monthly blood loss is expected combined with a decrease in dysmenorrhea compared to cyclic use of OCs. However, this seems to be related with a higher risk on spotting [28].

Due to potentially fewer side effects, improvement of societal productivity can be 4 expected in women receiving continuous OC treatment instead of GnRH agonist treatment. Moreover, since GnRH agonists are over 40 times more expensive than OCs, a reduction in directs costs of medication used in IVF/ICSI can be achieved by prolonged use of OCs prior to IVF/ICSI treatment.

Therefore, this study is conducted to investigate if continuous use of OC is non- inferior to long-term pituitary desensitization with a GnRH agonist (as standard care) combined with add-back therapy (if necessary) prior to IVF/ICSI treatment, with regard to treatment efficacy, safety and cost-effectiveness.

OUTCOMES The primary outcome is live birth rate after fresh embryo transfer (ET). Secondary outcomes are listed in Table 1. Measurements will be performed at baseline (t0), three (t1), six (t2), nine (t3), twelve (t4) and fifteen (t5) months after randomization.

MATERIALS AND METHODS

The study will have a parallel two-arm randomized controlled non-inferiority design and will be open-label. Recruitment of patients will be performed in two tertiary care centres in the Netherlands. The research population will consist of women with endometriosis ASRM Stage III or IV who are scheduled for their first, second or third IVF/ICSI treatment. The diagnosis of endometriosis has to be surgically confirmed or likely to be present based on transvaginal sonography (TVS) or magnetic resonance imaging (MRI) findings, including the presence of uni- or bilateral ovarian endometrioma and deep endometriosis. For diagnosing endometrial cysts and/or deep endometriosis

71 Chapter 4 diagnostic classification systems for imaging modalities like sonography and/or MRI do not exists, although guidelines help clinicians in describing sonographic findings in a structural way [30]. Clinics involved in this study will use the systematic approach for sonography as presented by the IDEA group [30]. Sonography and MRI are both shown to be accurate enough to diagnose endometrial cysts in the ovaries and deep endometriosis in the lower bowel and other pelvic structures [31]. Also women with surgically treated (i.e. remediated) moderate to severe endometriosis will be included. Excluded from participation will be women aged under 18 and over 41 years, women with a known contraindication for the use of OCs (history of venous thromboembolism (VTE), hepatic adenoma(s), positive family history for VTE and/or known thrombophilic abnormalities [32]) or for the use of GnRH agonists (severe side effects and/or allergic reaction to GnRH agonists), pregnant women, women with a malignancy or severe male factor infertility (i.e. azoospermia). Non-Dutch speaking women will be excluded. Women can only participate once in the study.

The study schedule is presented in the Consort Flow Diagram [Figure 1]. Before study entry, women will be screened for eligibility. Women who comply with all selection criteria will be informed about the trial during a visit at the outpatient clinic or IVF centre. Information will be handed out by a gynaecologist, resident, fertility physician or research nurse offering a reflection time of minimally 7 days. Informed consent must be signed before any study-related procedures can be carried out. After informed consent is obtained, women will be randomly assigned to the intervention group (one-phase oral contraceptive continuously administered during three subsequent months) or the reference group (three GnRH agonist depot injections during three subsequent months combined with add-back therapy if necessary). Randomization will be performed via web based randomly permuted blocks with variable, randomly chosen sizes (4–6–8 patients) stratified by participating centre. Drop outs after randomization will not be replaced.

After randomization, at baseline (t0) a TVS will be performed, to determine the presence of endometrioma and signs of deep endometriosis. Baseline characteristics and medical history will be listed in the case report file (CRF). Participants will be asked to complete different questionnaires at baseline (t0), three (t1), six (t2), nine (t3), twelve (t4) and fifteen (t5) months after randomization. These validated questionnaires measure quality of life of women with endometriosis (Endometriosis Health Profile 30 (EHP-30) [33]), direct and indirect medical costs (the Medical consumption Questionnaire (iMCQ) [34]) and the Productivity Cost Questionnaire (iPCQ) [35]). During the first 3 months of treatment medical consultation, side-effects and absence of work will also be recorded in a patients’ diary.

All women in the intervention group will receive one-phase oral contraceptives (sub- 50 OCs) continuously administered during three subsequent months (i.e. 3 × 28 days). Preferably ethinylestradiol/levonorgestrel 30/150 μg is prescribed. Since a lot

72 of patients already use specific types of OCs, other one-phase sub-50 OCs will be accepted as well. Women will be instructed to contact the IVF department on the first day of bleeding after stopping the OC (after 3 months) treatment. On day two of the withdrawal bleeding women will visit the IVF centre and Triptorelin ‘Decapeptyl’ s.c. will be started for suppression of the luteinizing hormone (LH) peak. One day later ovarian stimulation will be started with subcutaneously injected gonadotrophins (follicle stimulation hormone (FSH)) in an individually determined dosage.

All women in the reference group will receive three Leuprorelin ‘Lucrin’ 3.75 mg i.m. or s.c. depot injections during three subsequent months. During these months Tibolon ‘Livial’ 2.5 mg tablets can be given daily as add-back therapy. Women will have an appointment at the IVF department exactly 28 days after the last Leuprorelin injection. According to protocol, daily administration of Triptorelin ‘Decapeptyl’ s.c. will then be started. One day later ovarian stimulation will be started with subcutaneously injected gonadotrophins (FSH) in an individually determined dosage. 4 When the ovarian stimulation cycle is started women in both groups will be monitored routinely by standard (local) protocols, depending on follicle growth monitored by TVS. FSH dose adjustments during the stimulation cycle are allowed. Monitoring will be continued until the criteria for human chorionic gonadotrophin (hCG) injection are met (three or more follicles of 17 mm), to achieve final oocyte maturation. Oocyte retrieval will be carried out 34–37 h after hCG injection. Embryos will be cultured and incubated. Embryos will be morphologically assessed by combining the number of blastomeres and the percentage of fragmentation. The embryo with the highest number of blastocysts and the least fragmentation rate will be transferred 48–80 h after oocyte retrieval. The number of morphologic top-quality embryos (TQE) will be assessed and elective single embryo transfer (eSET) will be performed in the first IVF/ICSI cycle and ≤2 embryos will be selected for transfer to the uterus in the second or third cycle of IVF/ICSI. Remaining embryos of good quality will be cryopreserved according to local protocols. Luteal support and pregnancy testing will be accomplished by local protocols.

All additional IVF/ICSI treatment cycles (including subsequent pregnancies) up to 15 months after randomization (t5) will be registered in both intervention and control groups.

SAMPLE SIZE We performed a retrospective study regarding the efficacy and safety of IVF/ICSI in patients with moderate to severe endometriosis [36], showing ongoing pregnancy rates of 20% after fresh embryo transfer. De Ziegler et al. [22] reported clinical pregnancy rates of almost 40% in patients with moderate to severe endometriosis with or without the presence of an endometrioma during IVF with OCs as a pretreatment. Taking into account a miscarriage rate of 20% [37], an ongoing pregnancy rate of 30% can be

73 Chapter 4 expected after continuous use of OCs. Therefore, assuming that the ongoing pregnancy rate in patients treated with long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI is 20% and in patients treated with continuous use of OCs prior to IVF/ ICSI is 30%, 137 patients per group are sufficient to demonstrate an absolute difference of 13% (i.e. a non-inferiority margin of 3%) with an 80% power that the live birth rate in the continuous use of OCs group is not inferior to the live birth rate in the long-term pituitary desensitization with a GnRH agonists group. The non-inferiority margin of 3% is arbitrary chosen. Justification can be arranged by performing a discrete choice experiment taking into account efficacy, safety and burden of treatment. For instance, an earlier published trial concerning patients’ preference regarding GnRH agonist or antagonists in IVF/ICSI showed that with a trade-off of 2.0% increase in pregnancy rate patients would switch from antagonists to GnRH agonists [38]. Therefore, taking into account more benefits of oral contraceptives over GnRH agonists, a non-inferiority margin of 3% appears to be justified. The significance level is set at α 0.05, one sided. To take into account loss to follow-up due to withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure) the sample size is rounded off to 165 patients per group. In total, 330 patients need to be included in this study.

STATISTICAL ANALYSIS SPSS will be used for statistical analysis. Continuous data will be presented as means and standard deviations (normally distributed data) or medians and ranges (non-parametrical data). In case of dichotomous or categorical data numbers with percentages will be used.

The primary analysis (live birth rate after fresh embryo transfer) will be performed according to the intention to treat (ITT) principle including all randomized patients. The effectiveness of the interventional treatment versus the reference treatment will be expressed as a rate for live birth with corresponding 95% confidence interval. We will consider the intervention inferior when the absolute difference in success rate exceeds 13% compared to the expected success rate of 30% – this is comparable to a relative difference of 0.17/0.30 is 0.57. If the left border of the 95% CI of the RR does not exceed the pre-defined threshold of 0.57 for inferiority we will consider the intervention to be non-inferior to the reference treatment. A secondary analysis for effectiveness will be done on the per protocol (PP) population. Non-inferiority of the intervention is stated if non-inferiority is shown in both the ITT and PP population.

All secondary outcomes will be compared in both the ITT and PP analysis. The live birth rates in both groups will be compared using Kaplan–Meier analysis. Dichotomous and categorical data will be analysed using either Fisher Exact or chi-square as appropriate. For continuous outcomes, the confidence interval will be based on (the Welch version of) the t-test if the observations are normally distributed. If continuous

74 outcomes are non-normally distributed, the Mann–Whitney-U test will be employed. A probability (P) of less than 0.05 will be considered statistically significant. Because of the non-inferiority design of this study, for a better interpretation of the findings, confidence intervals around point estimates will also be provided.

An economic evaluation will be performed alongside the randomized controlled trial from a societal and a health care perspective according to Dutch guidelines with a time horizon of 15 months after randomization (i.e. 12 months after start of hormonal stimulation for IVF/ICSI treatment) [39].

Cost categories that will be included are: (1) healthcare costs (primary and secondary care, complementary care and home care); (2) lost productivity costs (absenteeism from paid and unpaid work, and presenteeism) and (3) patient costs (informal care and other care services paid for by patients themselves). Valuation will be done according to Dutch costing guidelines [40]. For the valuation of health care utilization, lost productivity and informal care Dutch standard costs will be used. Medication use 4 will be valued using prices of the Royal Dutch Society for Pharmacy. Patient and family costs other than informal care will be valued using self-reported prices. For the valuation of absenteeism from paid work, the friction cost approach will be used. To document absence from paid work the iPCQ [35] will be used at t0, t2 and t5. Besides, absence of work will be evaluated with a patient diary during the first 3 months of treatment.

The economic evaluation will be analysed by the ITT principle. Missing cost and effect data will be imputed using multiple imputation according to the MICE algorithm [41]. Rubin’s rules will be used to pool the results from the different multiply imputed datasets. Multiple regression analyses will be performed to estimate cost and effect differences between OC pre-treatment and the reference treatment of longterm pituitary desensitization with a GnRH agonist and adjusted for confounders. Incremental cost- effectiveness ratios (ICERs) will be calculated by dividing the difference in the mean total costs by the difference in mean effect between the two groups. Bias-corrected and accelerated bootstrapping with 5000 replications will be used to estimate 95% confidence intervals around the cost differences and statistical uncertainty surrounding the ICERs. Cost-effectiveness acceptability curves will also be estimated for a range of different ceiling ratios, thereby showing decision uncertainty [42].

In sensitivity analyses we will evaluate the effect of 50% higher or lower endometriosis- related complaints and/or side effects requiring surgery.

A budget impact analysis (BIA) is planned to be performed. The time horizon for the BIA will be 15 months after randomization up to the birth of a child. For our final BIA we will evaluate (I) a scenario where OCs will be implemented in all cases, (II) a scenario where OCs will be implemented in 70% of the cases and (III) sensitivity analyses on productivity loss.

75 Chapter 4

DATA MANAGEMENT AND MONITORING The datasets generated or analysed during the current study will be available from the corresponding author on reasonable request. An interim analysis for efficacy will not be performed. All Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the Medical Ethics Committee (METc). All Adverse Events (AEs) will be recorded and followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. An annual safety report will be send to the accredited METc and the competent authority. A Data Safety Monitoring Board (DSMB) will not be installed since all medication used in this study is registered for the given indication and used in clinical practice for years.

ETHICAL APPROVAL This study is approved by the National Central Committee on Research involving Human Subjects (CCMO – NL 59874.026.16) and by the METc of the VU University Medical Center (Ref. No. 2016.570). The trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl). From all participants written informed consent will be obtained before they will be enroled in the study.

DISCUSSION

In women with moderate to severe endometriosis, IVF/ICSI treatment is frequently applied to overcome endometriosis-associated infertility [43]. This randomized controlled trial is the first to investigate the non-inferiority and cost-effectiveness of continuous use of OCs compared to long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI treatment in women with endometriosis ASRM Stage III/ IV. An IVF/ICSI treatment strategy with continuous use of OCs holds promise to be more patient friendly as well as cost-effective compared with long-term pituitary desensitization with a GnRH agonist. To our knowledge there are currently no other (registered) ongoing trials that evaluate both treatment regimens.

The COPIE trial is an adequately powered trial. Since a new treatment regime (OCs) will be compared with the currently used standard treatment (GnRH agonist) a non- inferiority design is appropriate [44]. In case of a superiority design, a larger sample size (i.e. 650 women in total) would be needed, but this would not necessarily lead to different conclusions. If OC prior to IVF/ICSI is non-inferior, the current standard can be replaced and less women have to experience the discomforts that are related to the use of a GnRH agonist.

76 Due to the different application forms of GnRH agonist (subcutaneously or intramuscularly administered) and OCs (orally administered) the study will be open- labelled. This may influence the outcomes reported by the patient, like quality of life and the experienced side effects of both treatment regimens, but we do not expect the primary outcome to be influenced.

The risk of bias is reduced by random allocation of patients to the intervention or control group. Block-randomization, stratified for each participating centre, will be web based through which chance of allocation bias will be reduced.

To our best knowledge, it is unknown if add-back therapy has an effect on pregnancy rates after IVF/ICSI. Since the duration of pituitary desensitization is limited to 3 months, it is not obligatory to start with add-back therapy to reduce long-term side effects on bone mineral density. However, in clinical daily practice, add-back therapy can be necessary in patients receiving GnRH analogues, because of severe side effects (e.g. vasomotor complaints). Though, the hypothesis postulated by Barbieri 4 [45] supports the idea that endometriosis is effectively reduced in terms of endometrial growth and pain reduction by taking into account a threshold for serum estradiol of 30–50 pgram/ml. By using Tibolone 2.5 mg daily, as usually applied in add-back therapy, it is not expected that this threshold will be exceeded [46].

For this trial we use validated questionnaires in the Dutch language. The EHP-30 is a validated and frequently used instrument to measure quality of life in women diagnosed with endometriosis [33,47]. The iMCQ [34] and iPCQ [35] are validated questionnaires to measure medical consumption, absence from (paid) work and loss of productivity due to health problems and are both suitable to be used in chronic conditions like endometriosis.

The study is expected to guide future management of women with severe endometriosis undergoing IVF/ICSI, either (when continuous use of OCs is the preferred strategy) improving quality of life and treatment compliance or (when continuous use of OCs is inferior to GnRH agonists) preventing the use of strategy that reduces pregnancy rates.

Women and clinicians can use the results in shared-decision making, increasing the chance of pregnancy and with the potential to reduce healthcare expenditures. To improve counselling, a discrete choice experiment is planned to investigate patient preferences. We will evaluate the indirect costs of patients’ loss of societal productivity, due to endometriosis-related symptoms or medication associated side effects. The trial will be supported and promoted by the Dutch Endometriosis Foundation, the patient association for women with endometriosis in The Netherlands. By the intense collaboration with the Dutch Endometriosis Foundation and the NVOG (Dutch Society

77 Chapter 4 of Obstetrics & Gynaecology) Working Group on Endometriosis, the results of this trial should stimulate a prompt incorporation in guideline and daily practice. In 2015 this study was recognized by the NVOG as a first priority knowledge gap in reproductive medicine and is listed in the group of studies which are supported by the NVOG [48].

Figure 1 - Consort Flow Diagram and study schedule

Screening for potentially eligible Enrollment participants

Control of in- and exclusioncriteria

Randomization

Intervention group or control group

Intervention Control Allocation 3 months continuous use of 3 months long-term pituitary down regulation oral contraceptives GnRH agonist + add back therapy n = 150 n = 150

t0 baseline visit t0 baseline visit TVS, CRF TVS, CRF questionnaires: EHP‐30 / iMCQ / iPCQ questionnaires: EHP‐30 / iMCQ / iPCQ patient diary during the first three months patient diary during the first three months

Follow‐Up t1: 3 months after randomization withdrawal t1: 3 months after randomization bleeding after cessation of OCs, one day later 28 days after third Lucrin® injection start with start with Decapeptyl®, one day later Decapeptyl® one day later combined with FSH combined with FSH to start IVF/ICSI to start IVF/ICSI questionnaires: EHP-30 / iMCQ questionnaires: EHP-30 / iMCQ

t2: 6 months after randomization t2: 6 months after randomization questionnaires: EHP‐30 / iPCQ questionnaires: EHP‐30 / iPCQ t3: 9 months after randomization t3: 9 months after randomization question naires: EHP‐30 / iMCQ t4: questionnaires: EHP‐30 / iMCQ t4: 12 months after randomization 12 months after randomization questionnaires: EHP‐30 / iMCQ questionnaires: EHP‐30 / iMCQ

t5: 15 months after randomization End of trial t5: 15 months after randomization treatment outcomes treatment outcomes including additional IVF/ICSI cycles including additional IVF/ICSI cycles Questionnaires: EHP-30 / iMCQ / iPCQ Questionnaires: EHP-30 / iMCQ / iPCQ

CRF = case record form; EHP-30 = Endometriosis Health Profile 30; GnRH = gonadotropin releasing hormone; ICSI = intracytoplasmic sperm injection; iMCQ = iMTA Medical Consumption Questionnaire; iMTA = institute for Medical Technology Assessment; iPCQ = iMTA Productivity Cost Questionnaire; IVF = in vitro fertilization; n = number; t = time point; TVS = transvaginal sonography.

78 Table 1 – Secondary outcomes Secondary outcomes Clinical - Cumulative live birth rate after one IVF/ICSI treatment (number of live births per initiated cycle, including fresh and frozen ETs up to 15 months after randomization) - Ongoing pregnancy rate (positive heart action, confirmed > 10 weeks after ET by TVS) - Cumulative ongoing pregnancy rate (including fresh and frozen ETs up to 15 months after randomization) - Time to pregnancy (months) Treatment - Follicular development (follicle size distribution at the time of hCG administration) - Total dose and duration of gonadotrophin treatment - Number of oocytes and (top-quality) embryos (morphological assessment of embryos: combining number of blastomeres and percentage of fragmentation) - Fertilization rate (number of fertilized oocytes per number of retrieved oocytes) 4 - Implantation rate (number of embryonic sacs observed by TVS per number of transferred embryos) - Multiple pregnancy rate, miscarriage rate, ectopic pregnancy rate - Endometrial thickness (measured by TVS at the time of hCG administration) - Pain during oocyte pick up (VAS 0-10 cm) - Adverse events, complications, side-effects - Cancellation rate Endometriosis - Recurrence of endometriosis complaints within 15 months after randomization - Need for surgical/medical treatment within 15 months after randomization - Quality of life (EHP-30) - Patients’ preference of treatment and treatment-satisfaction (VAS 0-10 cm) Cost-effectiveness - Direct and indirect costs within 15 months after randomization and BIA (measured by the iMCQ and iPCQ validated questionnaires). Factors to be taken - Patient characteristics (age; BMI; smoking; alcohol use; hormonal into account treatment prior to start of study; duration until latest therapeutic surgery prior to start of study; prior surgical procedure; complete or incomplete remediation of endometriosis with prior surgery; presence of endometrioma and/or deep endometriosis on ultrasound and/or MRI; presence of adhaesions on ultrasound and/or MRI and/or during previous pelvic surgery; presence of adenomyosis diagnosed conform the MUSA criteria - Treatment characteristics (first/second/third IVF/ICSI attempt; other indications for IVF/ICSI) IVF = In Vitro Fertilization; ICSI = Intracytoplasmic Sperm Injection; EHP-30 = Endometriosis Health Profile 30; ET= Embryo Transfer; hCG = human Chorionic Gonadotrophin; TVS = Transvaginal Sonography; VAS = Visual Analogue Scale; BIA = budget impact analysis; iMCQ = iMTA Medical Consumption Questionnaire; iPCQ = iMTA Productivity Cost Questionnaire; iMTA = institute for Medical Technology Assessment; MUSA = Morphological Uterus Sonographic Assessment [49]

79 Chapter 4

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80 18. Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and metaanalysis. Fertil Steril. 2008;90:1055-1063. 19. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal addback in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24. 20. Zupi E, Marconi D, Sbracia M, et al. Add-back therapy in the treatment of endometriosis- associated pain. Fertil Steril. 2004;82:1303–1308. 21. van der Houwen LE, Schreurs AM, Schats R, Lambalk CB, Hompes PG, Mijatovic V. Patient satisfaction concerning assisted reproductive technology treatments in moderate to severe endometriosis. Gynecol Endocrinol. 2014;30:798-803. 22. de Ziegler D, Gayet V, Aubriot FX, et al. Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes. Fertil Steril. 2010;94:2796-2799. 23. Geukes M, van Aalst MP, Nauta MC, Oosterhof H. The impact of menopausal symptoms on work ability. Menopause. 2012;19:278-282. 24. De Graaff AA, D’Hooghe TM, Dunselman GA, Dirksen CD, Hummelshoj L, Simoens S. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international crosssectional survey. Hum Reprod. 2013;28:2677-2685. 4 25. Simoens S, Hummelshoj L, Dunselman G, Brandes I, Dirksen C, D’Hooghe T. Endometriosis cost assessment (the EndoCost study): a cost-of-illness study protocol. Gynecol Obstet Invest. 2011;71:170-176. 26. Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27:1292-1299. 27. Berlanda N, Somigliana E, Viganò P, Vercellini P. Safety of medical treatments for endometriosis. Expert Opin Drug Saf. 2016;15:21-30. 28. Hee L, Kettner LO, Vejtorp M. Continuous use of oral contraceptives: an overview of effects and sideeffects. Acta Obstet Gynecol. 2013;92:125–136. 29. Beyer-Westendorf J, Bauersachs R, Hach-Wunderle V, Zotz RB, Rott H. Sex hormones and venous thromboembolism – from contraception to hormone replacement therapy. Vasa 2018;47:441–450. 30. Guerriero S, Condous G, van den Bosch T, et al. Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. UltrasoundObstet Gynecol 2016;48:318–332. 31. Nisenblat V, Prentice L, Bossuyt PM, Farquhar C, Hull ML, Johnson N. Combination of the non-invasive tests for the diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;7:CD012281. 32. Middeldorp S. Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program. 2011; 2011:150-5. 33. Jones G, Jenkinson C, Kennedy S. Evaluating the responsiveness of the Endometriosis Health Profile Questionnaire: the EHP-30. Qual Life Res. 2004;13:705-713. 34. Bouwmans C. Manual iMTA Medical Consumption Questionnaire (iMCQ). 2013. Available from: www.imta.nl. Accessed June 26th 2018. 35. Bouwmans C. Manural iMTA Productivity Cost Questionnaire (iPCQ). 2013. Available from: www.imta.nl. Accessed June 26th 2018. 36. van der Houwen LE, Mijatovic V, Leemhuis E, et al. Efficacy and safety of IVF/ICSI in patients with severe endometriosis after long-term pituitary downregulation. Reprod Biomed Online. 2014;28:39-46.

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37. Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D. Women with advanced- stage endometriosis and previous surgery respond less well to gonadotropin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril. 2007;88:1568-1572. 38. van den Wijngaard L, van Wely M, Dancet EA, et al. Patients’ preferences for gonadotrophin- releasing hormone analogs in in vitro fertilization. Gynecol Obstet Invest. 2014;78:16–21. 39. Zorginstituut Nederland. Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidszorg. Diemen 2016 . Available from https://www.zorginstituutnederland.nl/ over-ons/publicaties/publicatie/2016/02/29/richtlijn-voor-het-uitvoeren-van-economische- evaluaties-in-degezondheidszorg. Accessed August 7th 2017. 40. Hakkaart-Van Roijen L, van der Linden N, Bouwmans C, Kanters T, Tan SS. Kostenhandleiding: Methodologie van kostenonderzoek en referentieprijzen voor economische evaluaties in de gezondheidszorg. Diemen 2016. Available from: https://www.zorginstituutnederland.nl/ over-ons/publicaties/publicatie/2016/02/29/richtlijn-voor-het-uitvoeren-van-economische- evaluaties-in-degezondheidszorg. Accessed August 7th 2017. 41. van Buuren S, Boshuizen HC, Knook DL. Multiple imputation of missing blood pressure covariates in survival analysis. Statistics in medicine. 1999;18:681-694. 42. Fenwick E, O’Brien BJ, Briggs A. Cost-effectiveness acceptability curves–facts, fallacies and frequently asked questions. Health economics. 2004;13:405-415. 43. Surrey ES. Endometriosis-Related Infertility: The Role of the Assisted Reproductive Technologies. Biomed Res Int. 2015;2015:482959. 44. Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308:2594-2604. 45. Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740–745. 46. Verheul HA, Blok LJ, Burger CW, Hanifi-Moghaddam P, Kloosterboer HJ. Levels of tibolone and estradiol and their nonsulfated and sulfated metabolites in serum, myometrium, and vagina of postmenopausal women following treatment for 21 days with tibolone, estradiol, or estradiol plus medroxyprogesterone acetate. Reprod Sci. 2007;14:160–168. 47. van de Burgt TJ, Hendriks JC, Kluivers KB. Quality of life in endometriosis: evaluation of the Dutchversion Endometriosis Health Profile-30 (EHP-30). Fertil Steril. 2011;95:1863-1865. 48. Oepkes D, Oudijk MA. Van Kennishiaten naar Wetenschaps-agenda; ambitie Koepel Wetenschap. Nederlands Tijdschrift voor Obstetrie & Gynaecologie. 2015;128:386-388. 49. van den Bosch T, Dueholm M, Leone FP, et al. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015;46:284–298.

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CHAPTER 5

Uterine bathing with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis, a multicenter randomized controlled trial

Lier, M.C.I. Özcan, H. Schreurs, A.M.F. Van de Ven, P.M. Dreyer, K. Van der Houwen, L.E.E. Johnson, N.P. Vandekerckhove, F. Verhoeve, H.R. Kuchenbecker, W. Mol, B.W. Lambalk, C.B. Mijatovic, V.

Accepted for publication Hum Reprod Open. Chapter 5

ABSTRACT

STUDY QUESTION What is the effect of uterine bathing with sonography gel prior to IVF/ICSI-treatment on live birth rates after fresh embryo transfer in patients with endometriosis?

SUMMARY ANSWER After formal interim analysis and premature ending of the trial, no significant difference between uterine bathing using a pharmacologically neutral sonography gel compared to a sham procedure on live birth rate after fresh embryo transfer in endometriosis patients (26.7% vs. 15.4%, relative risk (RR) 1.73, 95% confidence interval (CI) 0.81-3.72; p 0.147) could be found. The trial was however underpowered to draw definite conclusions.

WHAT IS KNOWN ALREADY Impaired implantation receptivity contributes to reduced clinical pregnancy rates after IVF/ICSI-treatment in endometriosis patients. Previous studies suggested a favorable effect of tubal flushing with Lipiodol® on natural conceptions. This benefit might also be explained by enhancing implantation through endometrial immunomodulation. Although recent studies showed no beneficial effect of endometrial scratching, the effect of mechanical stress by intrauterine infusion on the endometrium in endometriosis patients undergoing IVF/ICSI-treatment has not been investigated yet.

STUDY DESIGN, SIZE, DURATION We performed a multicenter, patient-blinded, randomized controlled trial in which women were randomly allocated to either a Gel Infusion Sonography (GIS, intervention group) or a sham procedure (control group) prior to IVF/ICSI-treatment. Since recruitment was slow and completion of the study was considered unfeasible, the study was halted after inclusion of 112 of the planned 184 women.

PARTICIPANTS/MATERIALS, SETTING, METHODS We included infertile women with surgically confirmed endometriosis ASRM stage I-IV undergoing IVF/ICSI-treatment. After informed consent, women were randomized to GIS with intrauterine instillation of ExEm-gel® or sonography with gel into the vagina (sham). This was performed in the cycle preceding the embryo transfer, on the day GnRH analogue treatment was started. Primary endpoint was live birth rate after fresh embryo transfer. Analysis was performed by both intention-to- treat and per-protocol.

MAIN RESULTS AND THE ROLE OF CHANCE Between July 2014 to September 2018, we randomly allocated 112 women to GIS (n=60) or sham procedure (n=52). The live birth rate after fresh embryo transfer was 16/60 (26.7%) after GIS versus 8/52 (15.4%) after sham (RR 1.73, 95% CI 0.81-3.72; p 0.147). Ongoing pregnancy rate was 16/60 (26.7%) versus 9/52 (17.3%, RR 1.54, 95% CI 0.74-3.18). Miscarriage occurred in 1/60

86 (1.7%) versus 5/52 (9.6%, RR 0.17, 95% CI 0.02-1.44) women. Uterine bathing resulted in a higher pain score compared with a sham procedure (VAS score 2.7 [1.3-3.5] vs. 1.0 [0.0-2.0], p<0.001). There were two adverse events after GIS versus none after sham procedures.

LIMITATIONS, REASONS FOR CAUTION The study was terminated prematurely due to slow recruitment and trial fatigue. Therefore, the trial is underpowered to draw definite conclusions regarding the effect of uterine bathing with sonography gel on live birth rate after fresh embryo transfer in endometriosis patients undergoing IVF/ ICSI-treatment.

WIDER IMPLICATIONS OF THE FINDINGS We could not demonstrate a favorable effect of uterine bathing procedures with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis.

STUDY FUNDING/COMPETING INTEREST(S) IQ Medical Ventures provided the ExEm FOAM® kits free of charge, they were not involved in the study design, data management, statistical analyses and/ or manuscript preparation etc. C.B.L. reports 5 receiving grants from Ferring, grants from Merck and grants from Guerbet outside the submitted work. C.B.L. is editor in Chief of Human Reproduction. V.M. reports grants and other from Guerbet outside the submitted work. B.W.M. reports grants from NHMRC (GNT1176437), personal fees from ObsEva, personal fees from Merck and Merck KGaA, personal fees from Guerbet and personal fees from iGenomix, outside the submitted work. N.P.J. reports research funding from Abb-Vie and Myovant Sciences and consultancy for Vifor Pharma, Guerbet, Myovant Sciences and Roche Diagnostics, outside the submitted work. K.D. reports personal fees from Guerbet, outside the submitted work. The other authors do not report any conflicts of interest. No financial support was provided.

TRIAL REGISTRATION NUMBER NL4025 (NTR4198)

TRIAL REGISTRATION DATE 7 October 2013

DATE OF FIRST PATIENT’S ENROLLMENT 22 July 2014

87 Chapter 5

INTRODUCTION

In patients with endometriosis, pregnancy and live birth rates after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment are reduced compared to patients without endometriosis [1-3]. This could be caused by a decreased quality of oocytes, a reduced implantation capacity of the embryo and/or a diminished endometrial receptivity [4-6]. Suggested explanations for the impaired endometrial receptivity of endometriosis patients undergoing IVF/ICSI-treatment are progesterone resistance, inflammation and inadequate decidualization as well as the presence of concomitant adenomyosis [3,5,7,8].

For nearly two decades, it has been hypothesized that applying local endometrial injury might induce a beneficial effect on endometrial receptivity, especially in patients with recurrent implantation failure (RIF) after IVF/ICSI-treatment [9-12]. Although multiple randomized controlled trials (RCTs) have investigated the effect of endometrial scratching prior to IVF/ICSI-treatment, the actual role of applying endometrial injury in women undergoing ART remains unclear [13]. A critical assessment of the quality of papers on endometrial scratching suggests that methodological problems may have biased the results of the trials [14].

As an alternative to scratching the endometrium, its receptivity might be modulated by infusing fluids into the uterine cavity (“uterine bathing”). In patients with minimal to mild endometriosis, undergoing hysterosalpingography (HSG) with Lipiodol®, an ethiodized oil derived from poppy seed, showed improved naturally conceived clinical pregnancy rates postprocedure [15]. Although this result is possibly explained by a flushing effect on the Fallopian tubes, a direct (therapeutic) effect on the endometrial receptivity was suggested as well. This hypothesis is supported by data from a randomized controlled animal study [16] in which treatment with Lipiodol® (versus infusion with saline versus sham treatment) altered the dendritic cell population of the endometrium in mice, suggesting a Lipiodol-induced favorable uterine immune response. Endometrial gene transcript regulation through Lipiodol® uterine bathing has also demonstrated a downregulation of endometrial Osteopontin, a molecule that could be interfering with implantation receptivity in women with endometriosis [17]. In order to investigate the effectiveness of pre-IVF uterine bathing with Lipiodol® in women with endometriosis or RIF, the IVF-LUBE trial was performed [18]. The study was, however, not sufficiently powered to show any difference between the intervention and control arm.

Beside a possible pharmacological mechanism of Lipiodol®, the favorable effects of uterine bathing could also be explained as the direct result of mechanical stress on the endometrium. In the available evidence, a control group treated with intrauterine saline or gel was not included and endometrial biopsies confirming the drug- therapeutic effect of Lipiodol® were absent. This hypothesis is partly supported by

88 the observations in limited quality trials that screening hysteroscopy, using intrauterine infusion, may increase IVF/ICSI pregnancy rates in some subpopulations [19-21].

In order to investigate the effect of mechanical pressure by intrauterine infusion of a pharmacological neutral sonography gel, on the endometrium in endometriosis patients (ASRM I-IV) undergoing IVF/ICSI treatment, we designed the TUBIE trial (Trial on Uterine Bathing before IVF/ICSI treatment in patients with Endometriosis). In the intervention arm of this randomized trial we performed a Gel Infusion Sonography (GIS) prior to IVF/ICSI treatment and in the control arm we applied a sham procedure. In both arms ExEm-gel® was used, a pharmacologically neutral gel, not containing any components which may enhance endometrial receptivity [22-24].

We hypothesized that in endometriosis patients scheduled for IVF/ICSI-treatment, uterine bathing with sonography gel would be superior to a sham procedure in terms of live birth rates after fresh embryo transfer, through a mechanical pressure mechanism inducing local injury of the endometrium. 5 MATERIAL AND METHODS

A multicenter, patient-blinded, parallel two-arm RCT was performed in four centers in the Netherlands and Belgium with special care for endometriosis. Participating centers were Amsterdam UMC (Location VUmc), Amsterdam, the Netherlands; OLVG, Amsterdam, the Netherlands; Isala, Zwolle, the Netherlands and Ghent University Hospital, Ghent, Belgium. The study was approved by the institutional review board of the Amsterdam UMC (Location VUmc); (METC VUmc reference number: 2013.242). The study had the acronym TUBIE trial (Trial on Uterine Bathing before IVF-/ICSI- treatment in patients with Endometriosis) and was registered in the Dutch Trial Register (NL4025 (NTR4198), 7 October 2013).

PATIENTS Infertile women aged 18-42 years with surgically confirmed endometriosis (American Society of Reproductive Medicine (ASRM), stage I-IV), scheduled for IVF/ICSI- treatment, were asked to participate by the investigators before the start of their IVF/ICSI treatment. Women with known anomalies of the uterus, a malignancy or a pregnancy were excluded.

RANDOMISATION & ALLOCATION After written informed consent, women were randomly assigned (1:1) to either a GIS procedure (intervention) or sham procedure (control). Randomization was performed without stratification in randomly permuted blocks of 2, 4 or 6, using a computer- generated randomization list. This randomization list was rendered by a statistician

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(P.M.v.d.V). All study procedures (intervention and control) were performed by investigators who were not involved in the IVF/ICSI-treatment. Patients, IVF clinic staff, embryologists and IVF technicians were blinded for the outcomes of randomization i.e. the performed study procedure and the subsequent IVF/ICSI-treatment.

INTERVENTIONS The study procedures (intervention or sham) were performed in the cycle preceding IVF/ICSI stimulation and embryo transfer, on the day GnRH analogue treatment was started [13] according to a standard long agonist protocol. Both procedures were performed by investigators who were not involved in the IVF/ICSI-treatment. For the GIS procedure, pharmacologically neutral ExEm-gel (GynaecologIQ/GISKIT, IQ Medical Ventures BV, Rotterdam, the Netherlands) was used [24]. A flexible catheter was placed through the internal ostium infusing a maximum amount of 10 mL gel in the uterine cavity. A transvaginal ultrasound, which was blinded for the patient, was performed immediately after infusing the gel. After performing the ultrasound the catheter was removed and the procedure was ended.

The sham procedure was performed in a similar way to the GIS procedure with the exception that the tip of the flexible catheter was placed in the vaginal posterior fornix, in order to avoid unintentional endometrial injury. After infusing a maximum amount of 10 mL ExEm-gel® intravaginally, a transvaginal ultrasound was performed. Again the ultrasound was blinded for the patient. After performing this, the procedure was ended by removal of the catheter.

IVF/ICSI PROCEDURE IVF/ICSI treatment procedures were performed by local protocol. In summary; at baseline (cycle day 2 or 3) a transvaginal sonography was performed. Patients started with oral contraceptives on the third day of the cycle for the total duration of three weeks. After two weeks pituitary down regulation by administration of GnRH agonists was started. GnRH agonists were continued till and including the day of hCG administration. Ovarian stimulation was performed according to the centers local protocol by recombinant FSH (rFSH) or highly purified human menopausal gonadotrophin (HP-HMG) (dosage individually determined) and was started on cycle day three. Patients were monitored routinely by a standard protocol, depending on the follicle growth. Monitoring was continued until the criteria for urinary hCG injection (Pregnyl® ) or recombinant hCG injection (Ovitrelle®) were met. Oocyte retrieval was carried out 34-37 hours after hCG injection. IVF/ICSI incubation procedures were performed according to the clinics standard practice. Embryo transfer (≤ 2 embryos) was performed 72-120 hours after oocyte retrieval. Remaining of good quality embryos were cryopreserved in nitrogen vapor tanks or in liquid nitrogen. Luteal support was accomplished by two capsules of 100mg Utrogestan per vaginam, three times a day,

90 during 15 days, or in case of pregnancy, 22 days. All medication was registered and marketed in the Netherlands and Belgium.

OUTCOMES The primary outcome was live birth rate after fresh embryo transfer. Secondary outcomes were biochemical pregnancy (increase in serum hCG), clinical pregnancy (gestational sac, with or without heartbeat, visible on ultrasound), ongoing pregnancy (viable intrauterine pregnancy that progresses beyond 12 weeks of gestation), multiple pregnancy (two or more gestational sacs, with or without heartbeat, visible on ultrasound), miscarriage (the presence of non-vitality on ultrasound or spontaneous loss of pregnancy before 12 weeks of gestation) and ectopic pregnancy (defined histologically if treated surgically or by clinical diagnosis if managed conservatively), all after the first cycle. If a pregnancy was terminated (medical assisted termination of pregnancy before 24 weeks of gestation), this was reported separately and not counted as live birth. Furthermore, adverse events of the procedure (such as infection and bleeding), pain experienced during the procedure (recorded using the visual analogue scale (VAS 0.0-10.0 cm)), complications of the IVF/ICSI-treatment, as well as complications during pregnancy and postpartum period, and neonatal outcomes were registered. 5

SAMPLE SIZE The sample size calculation was based on the data of the interim analysis of the IVF- LUBE trial [25]. To demonstrate an absolute difference of 20% in live birth rate between the two groups (20% in the sham group versus 40% in the GIS group) with a two-sided significance level of 5% and a power of 80%, 164 patients needed to be included in this trial. Considering a 10% loss to follow-up, the trial needed to include 92 patients per study group (184 patients in total).

STATISTICAL ANALYSIS The chi-square test or the Fishers’ exact test was used to compare dichotomous outcomes between the two arms of the trial. The relative risk (RR) is calculated as the effect size together with its 95% confidence interval (CI). The Student’s t-test or Mann Whitney U test (depending on the data distribution) was used to compare continuous outcomes between the arms. All statistics on primary and secondary outcomes were undertaken for the intention-to-treat (ITT) and per-protocol (PP) analysis. The statistical analysis was performed in IBM SPSS Statistics version 22.0 using a two- sided significance level of 5%.

Because of the slow accrual of this trial and the IVF-LUBE trial concluding that uterine bathing with Lipiodol® did not add to the success of IVF [18], it was decided to perform an interim analysis as soon as half of the planned study population had completed the study protocol. Details of the interim analysis were added to the trial protocol and approved by the institutional review board of the Amsterdam UMC (Location VUmc)

91 Chapter 5 before the required data became available. The interim analysis consisted of calculation of the conditional power which was defined as the probability of concluding live birth rate to be significantly higher in the GIS arm at the end of the trial given the planned sample size of 184 patients and the data observed so far. The conditional power was calculated under the assumption that the live birth rates in future participants in each of the two arms equalled those observed in the participants already included in the interim analysis. An independent statistician, who had no further involvement in the trial, performed the interim analysis as unblinding was considered necessary in order to avoid continuing the trial in case live birth rate was considerably smaller in the GIS arm.

RESULTS

Between July 2014 and September 2018, when the interim analysis was performed, a total of 113 women were included in this trial. After randomization, one patient was excluded from the trial as she did not meet the inclusion criteria [26]. She underwent a short stimulation IVF/ICSI protocol instead of the long stimulation protocol.

This trial started as a singlecenter study in Amsterdam. From the start, recruitment of participants was progressing slowly. Fewer women than initially expected fulfilled the in- and exclusion criteria of the study. This resulted in an adaptation of the inclusion criteria allowing all ASRM stages of endometriosis to be included (amendment to protocol approved by institutional review board of the Amsterdam UMC (Location VUmc)). Unfortunately, this was not enough to reach a sufficient amount of inclusions and lead to engage collaboration with three other large endometriosis care centers in the Netherlands and Belgium. However, even with this expansion, the inclusion rate remained slow, therefore it was decided to perform an interim analysis where conditional power would be used to decide on continuing or stopping the trial. At time of interim analysis, live birth rate was 24% (12/49) in the GIS group compared to 19% (8/43) in the sham group. Conditional power in case of continuing the trial was calculated as 4%. The conditional power was considered too low to warrant continuation of the trial and the trial was stopped for futility. Consequently, 112 women allocated to either uterine bathing by GIS (n=60) or a sham procedure (n=52) were included in the final analysis [Figure 1].

BASELINE CHARACTERISTICS Baseline characteristics are shown in Table 1. In all participants endometriosis was surgically confirmed: 65 women (58%) were diagnosed with minimal to mild endometriosis (ASRM stage I-II), 47 women (42%) with moderate to severe endometriosis (ASRM stage III-IV). Besides endometriosis, 52 women (46.6%) had concomitant reasons for infertility: male factor (total motile sperm count <1 x 10^6mL, n =27 (24.1%)), tubal factor (one- or two-sided, n = 23 (20.5%)), anovulation (n=7 (6.3%)) and cervical factor (n=2 (1.8%)). Seven couples (6.3%) had more than two reasons for infertility.

92 Table 1 – Baseline characteristics

GIS sham (n=60) (n=52) Age (years), median (IQR) 35 [33-39] 36 [33-38] BMI (kg/m2), median (IQR) 22.3 [20.2-23.9] 21.6 [20.8-24.2] Smoking, n(%) 3 (5.0) 1 (1.9) Ethnicity, n(%) 57 (95.0) 42 (80.8) - Caucasian 3 (5.0) 10 (19.2) - Non-Caucasian Gravidity, n(%) 23 (38.3) 25 (48.1) - 0 37 (61.7) 27 (51.9) - ≥ 1 Parity, n(%) 39 (65.0) 35 (67.3) - 0 21 (35.0) 17 (32.7) - ≥ 1 Miscarriage in obstetric history, n(%) 22 (36.7) 17 (32.7) Curettage in obstetric history, n(%) 4 (6.7) 6 (11.5) EUG in obstetric history, n(%) 2 (3.3) 2 (3.8) 5 Stage of endometriosis (rASRM), n(%) 30 (50.0) 35 (67.3) - Minimal / Mild (I/II) 30 (50.0) 17 (32.7) - Moderate / Severe (III/IV) Average cycle duration (days), median (IQR) 28 [28-30] 28 [28-30] Total number of AFC on cycle day 2-4 mean (± SD) 15 ± 6 11 ± 6 Months of infertility mean (± SD) 44.2 ± 26.8 35.3 ± 18.1 Previous MAR in current child wish, n(%) 54 (90.0) 48 (92.3) IVF/ICSI cycle number, median (IQR) 2 [1-2] 1 [1-2]

AFC = Antral Follicle Count; BMI = Body Mass Index; EUG = extra uterine gravidity; GIS = Gel Infusion Sonography; IQR = Interquartile Range; MAR = Medically Assisted Reproduction; n = number; rASRM = revised American Society for Reproductive Medicine; SD = standard deviation.

Of the women randomized for GIS, one participant cancelled the procedure and did not receive the allocated treatment. In the sham group, one procedure failed as gel was infused into the uterine cavity during the procedure. Of the 59 women who underwent a GIS procedure, 12 did not undergo fresh embryo transfer after completing the IVF/ ICSI-treatment, including 5 with a poor response, 4 with a hyper response or 2 women with total fertilization failure. In the group of the sham procedure, five women had a poor response and one a hyper response resulting in a cancelled fresh embryo transfer. As a result 48/60 women (80%) in the GIS group and 45/52 women (86.5%) in sham procedure group underwent a fresh embryo transfer. There was no loss to follow up.

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PAIN SCORES The median pain scores, measured by a VAS (0.0 - 10.0 cm) directly after the procedure, were significantly higher following GIS 2.7 cm (25th – 75th percentiles 1.3 - 3.5) than following sham procedure 1.0 cm (0.0 - 2.0, p <0.001). There were two adverse events after a GIS procedure. One woman fainted during the procedure because of excessive pain (VAS 10.0cm), another woman suffered from non-severe vaginal blood loss for a day after the procedure [Table 2].

Table 2 – Investigational procedure characteristics

GIS sham p-values (n = 60) (n=52) Amount gel infused (mL), median (IQR) 6.0 [5.0-7.0] 5.0 [4.0-5.5] 0.003* Procedure time (min.), mean (± SD) 9.3 ± 2.7 8.5 ± 2.0 0.089 Cervical leakage, n (%) 13 (21.7) NA - VAS score (cm), median (IQR) 2.7 [1.3-3.5] 1.0 [0.0-2.0] <0.001* Adverse event, n (%) 2 (3.3) 0 (0.0) 0.173

IQR = Interquartile Range; n = number; NA = not applicable; SD = standard deviation; VAS = Visual Analog Scale. *p-value < 0.05.

IVF/ICSI-TREATMENT The IVF- or ICSI-treatment characteristics are presented in Table 3. There were no significant differences between the groups. Six women randomized for a GIS procedure had a complication of the IVF/ICSI-treatment: four women were diagnosed with mild-to-moderate ovarian hyperstimulation syndrome (OHSS) [27]; one women was diagnosed with an ectopic pregnancy for which a laparoscopic tubotomy was undertaken; and one women was diagnosed with an ovarian torsion in pregnancy at six weeks and six days of gestation then underwent a laparoscopy and the pregnancy continues successfully.

94 Table 3 - IVF-/ICSI treatment characteristics

GIS sham p-values (n = 60) (n = 52) Treatment type, n (%) 0.286 - IVF 42 (70.0) 41 (78.8) - ICSI 18 (30.0) 11 (21.2) Cycle number, median (IQR) 2 [1-2] 1 [1-2] 0.029* Endometrial thickness at day of hCG (mm), 3.9 [2.8-5.9] 4.0 [2.9-5.3] 0.751 median (IQR) Dose FSH (U), median (IQR) 2225 [1663-2925] 2475 [1650-2925] 0.460 Semen, gain after processing (*106), median 14.0 [4.5-49] 20.0 [8.0-49.0] 0.339 (IQR) Number of retrieved oocytes, median (IQR) 10 [7-14] 8 [5-13] 0.160 Number of fertilized oocytes, median (IQR) 6 [4-8] 5 [3-9] 0.333 Number of embryos for transfer, median (IQR) 5 [4-8] 4 [2-8] 0.333 Number of transferred embryos, n (%) 0.126 - No embryo transferred 12 (20) 6 (11.5) - SET 40 (66.7) 43 (82.7) 5 - DET 8 (13.3) 3 (5.8) Top-quality of transferred embryo, n (%) - Embryo 1 18 (45.0) 17 (39.5) 0.895 - Embryo 2 (in case of DET) 2 (25.0) 0 (0.0) 0.338 Blastocyst transfer, n (%) 2 (3.3) 1 (1.9) 0.645 Cryopreservation, n (%) 43 (71.7) 34 (65.4) 0.097 Number of frozen embryos, median (IQR) 4 [2-7] 4 [1-7] 0.277 Complications, n (%) 6 (10.0) 1 (1.9) 0.081 - OHSS (mild/moderate) 4 (6.7) 1 (1.9) - Ectopic pregnancy 1 (1.7) 0 (0.0) - Ovarian torsion 1 (1.7) 0 (0.0)

DET = Double Embryo Transfer; FSH = Follicle Stimulating Hormone; GIS = Gel Infusion Sonography; hCG = human Chorionic Gonadotropin; IVF = In Vitro Fertilization; ICSI = Intracytoplasmic Sperm Injection; mm = millimeter; n = number; OHSS = Ovarian Hyperstimulation Syndrome; SET = Single Embryo Transfer; U = units. *p-value < 0.05.

In the sham group only one women had a complication of the IVF/ICSI-treatment, showing signs of a mild-to-moderate OHSS (p=0.081).

PREGNANCY OUTCOMES

Intention to treat (ITT) analysis The primary outcome live birth rate per patient was 16/60 (26.7%) in the GIS group compared to 8/52 (15.4%) in the sham group (RR 1.73, 95% CI 0.81-3.72, p = 0.147)

95 Chapter 5

[Table 4]. Secondary outcome measures are listed in Table 4. Adjustment for baseline characteristics (ethnicity, AFC, duration infertility and cycle number), had no impact on the results (not reported). Two sensitivity analyses were performed; a first sensitivity analysis in which the excluded patient (n=1) was included in the analysis and a second sensitivity analysis in which we counted the woman in the control group who had her pregnancy terminated because of trisomy 21 as live birth. Conclusion of the ITT analysis remained unchanged for both the sensitivity analyses.

Table 4 – Primary and secondary outcome measures; pregnancy outomes after fresh embryo transfer (ITT analysis)

GIS sham p-values Relative risk 95% CI for (n=60) (n=52) (RR) the RR Primary outcome, n (%) - Live birth 16 (26.7) 8 (15.4) 0.147 1.73 (0.81-3.72) Secondary outcome, n (%) - Biochemical pregnancy 24 (40.0) 18 (34.6) 0.557 1.16 (0.71-1.88) - Clinical pregnancy 17 (28.3) 14 (26.9) 0.868 1.05 (0.58-1.92) - Ongoing pregnancy 16 (26.7) 9 (17.3) 0.236 1.54 (0.74-3.18) - Multiple pregnancy 1 (1.7) 0 (0.0) - - - - Miscarriage 1 (1.7) 5 (9.6) - - - - Ectopic pregnancy 1 (1.7) 0 (0.0) - - - - Termination of pregnancy 0 (0.0) 1 (1.9) - - -

CI = Confidence Interval; GIS = Gel Infusion Sonography; ITT = Intention-to-treat; n = number; RR = Relative Risk.

Per protocol (PP) analysis When analyzed per protocol, live birth rate after fresh embryo transfer in the GIS group was 16/48 (33.3%) versus 8/45 (17.8%) (RR 1.80, 95% CI 0.84-3.82, p 0.117). Secondary outcome measures of the PP analysis are shown in Table 5.

96 Table 5 – Primary and secondary outcome measures; pregnancy outcomes after fresh embryo transfer (PP analysis)

GIS sham p-values Relative risk 95% CI for (n= 48) (n= 45) (RR) the RR Primary outcome, n (%) - Live birth 16 (33.3) 8 (17.8) 0.117 1.80 (0.84-3.82) Secondary outcome, n (%) - Biochemical pregnancy 24 (50) 15 (33) 0.104 1.50 (0.91-2.48) - Clinical pregnancy 17 (35.4) 12 (26.7) 0.363 1.33 (0.72-2.46) - Ongoing pregnancy 16 (33.3) 8 (17.8) 0.087 1.88 (0.89-3.95) - Multiple pregnancy 1 (2.1) 0 (0.0) - - - - Miscarriage 1 (2.1) 4 (8.9) - - - - Ectopic pregnancy 1 (2.1) 0 (0.0) - - - - Termination of pregnancy 0 (0.0) 0 (0.0) - - -

CI = Confidence Interval; GIS = Gel Infusion Sonography; n = number; PP = Per-protocol; RR = Relative Risk. 5 PREGNANCY, POSTPARTUM AND NEONATAL OUTCOMES Pregnancy outcomes and postpartum period are shown in Table 6. One woman in the in the control group had her pregnancy terminated because of trisomy 21. In the intervention group, five pregnancy complications were reported: two women developed hypothyroidism; two women were diagnosed with gestational diabetes and a placenta previa and one women was diagnosed with pre-eclampsia. In the sham group, two complications of pregnancy were reported; one woman had gestational diabetes and one woman with fetomaternal transfusion. There were four postpartum complications in the intervention group; three postpartum hemorrhage and one bladder lesion during cesarean section, and one woman in the sham group had a postpartum curettage because of retained products of conception. There was no significant difference in neonatal outcomes between both groups. In the intervention group one child was admitted to the Neonatal Intensive Care Unit (NICU) because of respiratory distress syndrome after premature birth.

Table 6 – Follow-up of pregnancy and postpartum period

GIS sham p-values (n = 16) (n = 8) Complications during pregnancy, n (%) 5 (31.3) 2 (25.0) 0.750 Postpartum complications, n (%) 4 (25.0) 1 (12.5) 0.477 Gestational age (weeks + days), median (IQR) 39+3 [37+6 – 40+1] 40+0 [37+5 – 40+2] 0.787 Prematurity, n (%) 1 (6.3) 0 (0.0) - NICU admittance, n (%) 1 (6.3) 0 (0.0) -

GIS = Gel Infusion Sonography; IQR = Interquartile range; n = number; NICU = Neonatal Intensive Care Unit.

97 Chapter 5

DISCUSSION

The TUBIE trial investigated the effect of uterine bathing using ExEm-gel® on live birth rates after fresh embryo transfer in endometriosis patients undergoing IVF/ICSI- treatment. Regarding the primary outcome, no significant differences were found between patients randomized for intervention and sham procedures (26.7% vs. 15.4%, RR 1.73, 95% CI 0.81-3.72; p value 0.147). The study was terminated prematurely after a formal interim analysis was performed when 50% of the planned study population had completed the study protocol.

The main strength of the TUBIE trial was the patient-blinded randomized controlled study design and the analysis on both intention-to-treat and per-protocol basis. All study procedures (intervention and control) were performed with a pharmacologically neutral gel by investigators who were not involved in the IVF-/ICSI-treatment procedures. Additionally, patients were blinded for the received treatment, since a sham procedure was performed in the control group. Despite this blinding, it should be noted that the GIS procedure and sham procedure might have been experienced differently by the patients, given the fact that the median pain scores measured immediately after the procedure, were significantly higher after GIS compared to that after the sham procedure.

The main weakness was the unplanned interim analysis and the insufficient power of the trial. When initiating the TUBIE trial, we stated that a 20% improvement in live birth rate in patients receiving GIS procedure was needed to accept the intervention. However, at the time of the interim analysis, a 5% improvement was shown in the GIS group (GIS vs. sham; 24% vs. 19%). Conditional power in case of continuing the trial was calculated as 4%, which was considerably less than the 90% which was the preset minimum value for further continuation of the trial. A high threshold of 90% was chosen and described in an amendment to protocol, approved by the institutional review board, because of the considerable trial fatigue which made it only feasible to continue the trial in case of very promising interim results. It must be noted that generally much lower thresholds for the conditional power, around 20-30%, are used to guide stopping for futility. However, also if a lower threshold for the conditional power was chosen, the trial would still have been stopped early for futility since the conditional power at the interim analysis was only 4%.

After terminating the trial, there was a difference of 11.3% in live birth rate between the groups (26.7% vs. 15.4%). However, this difference in live birth rate was not statistically significant. Since the study is underpowered, drawing firm conclusions regarding the effect of uterine bathing with a pharmacologically neutral gel on live birth rates after fresh embryo transfer in patients with endometriosis undergoing IVF/ ICSI-treatment is impossible. The 20% improvement used in the original power analysis

98 was based on interim data of the IVF-LUBE trial [25]. In hindsight, this improvement was overoptimistic.

The idea that local endometrial injury might induce a positive effect on endometrial receptivity was first suggested by Granot et al. (2000) [28]. Since then multiple studies were performed to investigate this effect, reporting either positive, negative, or neutral trial results [12, 29]. Up till now, a convincing beneficial effect of endometrial scratching has not been established. The most recent systematic review still report high clinical and statistical heterogeneity in the included trials with no differences between scratch and controls with respect to live birth and clinical pregnancy rates [13]. In addition, the recently published randomized trial of Lensen et al. (2019) [30] including 1364 women undergoing endometrial scratching prior to IVF treatment is in line with these findings and did not report higher live birth rates after scratching. Among the study population of this trial, 7.9% were endometriosis patients (n=108). Subgroup analysis also showed no beneficial effect of endometrial scratching prior to IVF/ICSI-treatment on live birth rate in endometriosis patients as well. Although endometrial scratching is currently the most offered IVF add-on in the UK [31], the risk of harm should also be considered. Therefore this add-on is currently rated amber by the Human Fertilisation 5 and Embryology Authority (HFEA) [32].

Theoretically, local injury of the endometrium might also be applied by infusion of intra-uterine fluids or gels. Since previous studies suggested that uterine bathing with Lipiodol® might have an effect on endometrial receptivity by immunomodulation [16,17,33], we aimed to investigate the effect of mechanical stress on the endometrium by uterine bathing with an pharmacologically neutral non-embryotoxic gel (ExEm- gel®). ExEm-gel® is frequently used during fertility work-up and is registered and marketed in the Netherlands for GIS procedures [24]. To the best of our knowledge ExEm-gel® does not contain potential therapeutic components which may enhance endometrial receptivity [22-24]. And although observations in limited quality trials suggest that screening hysteroscopy might improve IVF/ICSI-treatment results [19- 21], performing uterine bathing with ExEm-gel® is not endorsed by our study results. This is in accordance to the final report of the LUBE trial [18] in which no difference in success rates for IVF following uterine bathing with Lipiodol® for women with endometriosis or RIF could be found. The trail of Salehpour et al. (2016) [34] in which intrauterine saline infusion as a form of endometrial injury was performed during IVF treatment even showed a negative effect on clinical pregnancy numbers and implantation rates among patients with RIF.

The recent insights that applying endometrial injury does not positively affect reproductive outcomes in patients undergoing IVF/ICSI-treatment is supported by the results of our TUBIE trial. Overall, the biological plausibility of performing endometrial injury procedures to improve endometrial receptivity can be questioned [35]. The

99 Chapter 5 various hypotheses that might explain the beneficial effect of applying endometrial injury have never been shown nor proven by a plausible biological influence on the endometrium and its effect on implantation. Evidence is derived from trials with high clinical and statistical heterogeneity and the investigated procedures (scratching, uterine bathing and screening hysteroscopy) injured the endometrium in different ways. Additionally, methodological issues are common in the majority of RCTs reporting on endometrial scratching, leading to biased trial results [14]. Therefore the results cannot simply be merged and compared together in a straight forward way. Furthermore, these invasive procedures can be painful and may lead to adverse events.

CONCLUSION

In conclusion, in this prematurely terminated and therefore underpowered multicenter RCT, we found no favorable effect of uterine bathing using a pharmacologically neutral gel compared to a sham procedure prior to IVF/ICSI-treatment on live birth rates after fresh embryo transfer in patients with endometriosis. Uterine bathing procedures were associated with higher pain scores and a small number of adverse events. Therefore, uterine bathing procedures are not advised as routine add-on to IVF/ICSI-treatment in women with endometriosis.

100 REFERENCES

1. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148-1155. 2. Harb HM, Gallos ID, Chu J, Harb M, Coomarasamy A. The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis. BJOG. 2013;120:1308-1320. 3. Muteshi CM, Ohuma EO, Child T, Becker CM. The effect of endometriosis on live birth rate and other reproductive outcomes in ART cycles: a cohort study. Hum Reprod Open. 2018;2018: hoy016. 4. Pellicer A, Navarro J, Bosch E, et al. Endometrial quality in infertile women with endometriosis. Ann N Y Acad Sci. 2001;943:122-130. 5. Brosens, I, Brosens JJ, Benagiano G. The eutopic endometrium in endometriosis: are the changes of clinical significance? Reprod Biomed Online. 2012;24:496-502. 6. Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why. Fertil Steril. 2017;108:19-27. 7. Revel A. Defective endometrial receptivity. Fertil Steril. 2012;97:1028-1032. 8. Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014;29:964-977. 9. Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium 5 doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003;79:1317-1322. 10. Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril. 2008;89:1166-1176. 11. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25:561-571. 12. Nastri CO, Lensen SF, Gibreel A, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2015:CD009517. 13. van Hoogenhuijze NE, Kasius JC, Broekmans FJM, Bosteels J, Torrance HL. Endometrial scratching prior to IVF; does it help and for whom? A systematic review and meta-analysis. Hum Reprod Open. 2019;2019:hoy025. 14. Li W, Suke S, Wertaschnigg D, et al. Randomised controlled trials evaluating endometrial scratching: assessment of methodological issues. Hum Reprod. 2019;34:2372-2380. 15. Johnson NP, Farquhar CM, Hadden WE, Suckling J, Yu Y, Sadler L. The FLUSH trial--flushing with lipiodol for unexplained (and endometriosis-related) subfertility by hysterosalpingography: a randomized trial. Hum Reprod. 2004;19:2043-2051. 16. Johnson NP, Bhattu S, Wagner A, Blake DA, Chamley LW. Lipiodol alters murine uterine dendritic cell populations: a potential mechanism for the fertility-enhancing effect of lipiodol. Fertil Steril. 2005;83:1814-1821. 17. Johnson NP, Baidya S, Jessup SO, et al. Randomised trial of Lipiodol Uterine Bathing Effect (LUBE) in women with endometriosis-related infertility. Fertil Reprod. 2019;1:57-64. 18. Reilly SJ, Glanville EJ, Dhorepatil B, Prentice LR, Mol BW, Johnson NP. The IVF-LUBE trial - a randomized trial to assess Lipiodol(®) uterine bathing effect in women with endometriosis or repeat implantation failure undergoing IVF. Reprod Biomed Online. 2019;38:380-386. 19. Bosteels J, Weyers S, Puttemans P, et al. The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review. Hum Reprod Update. 2010;16:1-11.

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20. Karayalçin R, Ozyer S, Ozcan S, et al. Office hysteroscopy improves pregnancy rates following IVF. Reprod Biomed Online. 2012;25:261-266. 21. Kamath MS, Bosteels J, D’Hooghe TM, et al. Screening hysteroscopy in subfertile women and women undergoing assisted reproduction. Cochrane Database Syst Rev. 2019:CD012856. 22. Exalto N, Stappers C, van Raamsdonk LAM, Emanuel MH. Gel instillation sonohysterography: first experience with a new technique. Fertil Steril 2007;87:152-155. 23. Emanuel MH, van Vliet M, Weber M, Exalto N. First experiences with hysterosalpingo-foam sonography (HyFoSy) for office tubal patency testing. Hum Reprod. 2012;27:114-117. 24. Exalto N, Stassen M, Emanuel MH. Safety aspects and side-effects of ExEm-gel and foam for uterine cavity distension and tubal patency testing. Reprod Biomed Online. 2014;29:534-540. 25. Reilly SJ, Stewart AW, Prentice LR, Johnson NP. The IVF-Lube Trial: Lipiodol uterine bathing effect for enhancing the results of in vitro fertilisation, a pilot randomised trial. Abstract of the 11th World Congress on Endometriosis 2011, S10-5. 26. Fergusson D, Aaron SD, Guyatt G, Hébert P. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ. 2002;325:652-654. 27. Navot D, Bergh PA. Ovarian hyperstimulation syndrome: a practical approach. In: Ovarian endocrinopathies. The proceedings of the 8th Reinier de Graaf Symposium, Amsterdam, 2-4 september 1993;215-225. 28. Granot I, Dekel N, Bechor E, Segal I, Fieldust S, Barash A. Temporal analysis of connexin43 protein and gene expression throughout the menstrual cycle in human endometrium. Fertil Steril. 2000;73:381-386. 29. Panagiotopoulou N, Karavolos S, Choudhary M. Endometrial injury prior to assisted reproductive techniques for recurrent implantation failure: a systematic literature review. Eur J Obstet Gynecol Reprod Biol. 2015;193:27–33. 30. Lensen S, Osavlyuk D, Armstrong S, et al. A Randomized Trial of Endometrial Scratching before In Vitro Fertilization. N Engl J Med. 2019;380:325-334. 31. Spencer EA, Mahtani KR, Goldacre B, Heneghan C. Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ Open. 2016;6:e013940. 32. Lensen S, Shreeve N, Barnhart KT, Gibreel A, Ng EHY, Moffett A. In vitro fertilization add-ons for the endometrium: it doesn’t add-up. Fertil Steril. 2019;112:987-993. (b) 33. Johnson NP. Review of lipiodol treatment for infertility - an innovative treatment for endometriosis-related infertility? Aust N Z J Obstet Gynaecol. 2014;54:9-12. 34. Salehpour S, Zamaniyan M, Saharkhiz N, et al. Does intrauterine saline infusion by intrauterine insemination (IUI) catheter as endometrial injury during IVF cycles improve pregnancy outcomes among patients with recurrent implantation failure?: An RCT. Int J Reprod Biomed (Yazd). 2016;14:583-588. 35. Simón C, Bellver J. Scratching beneath ‘The Scratching Case’: systematic reviews and meta- analyses, the back door for evidence-based medicine. Hum Reprod. 2014;29:1618-1621.

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103

Part II

Pathophysiological aspect of endometriosis in pregnancy

CHAPTER 6

Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series

Lier, M.C.I. Malik, R.F. Van Waesberghe, J.H.T.M. Maas, J.W. Van Rumpt – Van de Geest, D.A. Coppus, S.F. Berger, J.P. Van Rijn, B.B. Janssen, P.F. De Boer, M.A. De Vries, J.I.P. Jansen, F.W. Brosens, I.A. Lambalk, C.B. Mijatovic, V.

BJOG. 2017;124:306-312 Chapter 6

ABSTRACT

OBJECTIVE To report pregnancy outcomes of SHiP (spontaneous haemoperitoneum in pregnancy) and the association with endometriosis.

DESIGN Retrospective case note review.

SETTING Dutch referral hospitals for endometriosis.

SAMPLE Eleven women presenting with 15 events of SHiP.

METHODS In collaboration with the Dutch Working Group on Endometriosis, unpublished cases of SHiP that occurred in the Netherlands between 2010 and 2015 were retrieved.

MAIN OUTCOME MEASURES Maternal and perinatal mortality and morbidity.

RESULTS SHiP occurred predominantly in the second and third trimester of pregnancy. The earliest and major presenting symptom was an acute onset of abdominal pain, often combined with low haemoglobin levels or signs of fetal distress. Imaging was a diagnostic tool when free peritoneal fluid could be observed. For surgical treatment of the bleeding site, a midline laparotomy was mostly needed, the median estimated amount of blood loss was 2000 mL. No fetomaternal or perinatal mortality was reported, despite a high rate of preterm births (54.5%). In all women, endometriosis was diagnosed at a certain moment in time and therefore probably involved in the pathogenesis of SHiP. Four women showed recurrence of SHiP. In one of these cases the second event of SHiP occurred in a subsequent pregnancy.

CONCLUSION Pregnancy outcomes of SHiP are improving when compared with previous reports, with absent fetomaternal and perinatal mortality in this recent series. Growing knowledge and adequate multidisciplinary intervention may have contributed to these favourable results. Increasing awareness of this serious complication of pregnancy is advocated, especially in women diagnosed with endometriosis.

108 INTRODUCTION

Spontaneous haemoperitoneum in pregnancy (SHiP) is a rare but potentially life- threatening complication which occurs predominantly during the third trimester of pregnancy [1]. SHiP is associated with adverse pregnancy outcomes for both mother and child [2,3].

Until 1950 a high maternal mortality rate after SHiP was reported (around 50%), reaching up to 76.3% in women giving birth [4,5]. Ginsburg et al. were the first to describe a dramatically decreased maternal mortality rate of 4% in 1987 [1]. Thereafter, Brosens et al. [4] showed an absence of maternal deaths following SHiP in 25 cases. Despite this reduction in maternal mortality in the last centuries, perinatal mortality remained high (36%) until recently [6].

The aetiology of SHiP is still unknown but endometriosis seems to be a major risk factor [6,7]. As pregnancies in subfertile women diagnosed with endometriosis are more often facilitated by assisted reproductive techniques [8–11], the incidence of SHiP may increase. To raise awareness of this diagnosis among clinicians, we collected unpublished data from 11 women presenting with 15 events of SHiP. 6

METHODS

In collaboration with the members of the Dutch Working Group on Endometriosis, a Special Interest Group (SIG) of the Dutch Society of Obstetrics & Gynaecology (NVOG), Dutch gynaecologists in referral hospitals for endometriosis were contacted and asked to send in unpublished cases of SHiP that occurred in the Netherlands in recent years. Nine hospitals identified cases of SHiP and data were retrieved from the original patient files. Information on patient characteristics, symptoms of SHiP, treatment options and outcomes for mother and child was obtained. No approval of the institutional review board was required for this report. Patients’ written consent for publication was obtained in all cases.

RESULTS

Fifteen events of SHiP that occurred in the Netherlands between 2007 and 2015 in 11 women were identified. Patient characteristics, symptoms, treatment and maternal as well as neonatal outcome parameters are depicted in Table 1. Mean age at initial SHiP event was 34 years (median 34 years, range 27–38 years). The onset of SHiP varied from 6 weeks of gestation to 30 days postpartum. Four women showed recurrence of SHiP; in one of these cases the second event of SHiP occurred in a subsequent

109 Chapter 6 pregnancy. In all women, endometriosis was diagnosed at a certain moment in time: eight women were known to have surgically confirmed severe endometriosis prior to pregnancy. Three women were diagnosed with endometriosis after SHiP; in two cases the diagnosis was confirmed after histological examination of the biopsied specimens and in one case the presence of deep endometriosis was visualized post-operatively by magnetic resonance imaging (MRI). All women presented with acute abdominal pain often combined with low haemoglobin levels (n = 8), a sign of substantial blood loss. None of the cases reported a history of trauma, previous caesarean section, recent physical activity or sexual intercourse. In most SHiP events, free peritoneal fluid was detected by ultrasound examination (n = 10), MRI (n = 2) or computed tomography angiography (n = 1). Surgical intervention (n = 13) in pregnancy (n = 11) was necessitated for maternal reasons (signs of hypovolaemic shock, progressive anaemia or suspicion of a haemoperitoneum, n = 7), fetal distress (abnormal cardiotocography, n = 2) or a combination of both (n = 2). Laparoscopy was initially performed in five cases, but had to be converted into a laparotomy because the bleeding sites could not be reached or extensive bleeding caused blurred vision. The median estimated amount of blood loss was 2000 mL. Bleeding lesions were predominantly of venous origin and located at the broad ligaments, left utero-sacral ligament or posterior side of the uterus [Figure 1]. Usually, suture-ligation combined with the application of haemostatic agents was sufficient to achieve haemostasis. In the majority of cases a surgeon was involved in the treatment of SHiP because of extensive adhesions and/or intestinal involvement due to endometriosis or the suspicion of ruptured large intra-abdominal vessels. Two cases did not require immediate surgical intervention and expectant management was chosen. In four cases a biopsy from the bleeding site was obtained; all biopsies showed signs of decidualization and haemorrhagic foci of endometriosis at histologic examination. Postnatal resuscitation and subsequent admission to the neonatal intensive-care unit (NICU) was necessary in one case. Four other neonates were admitted to the NICU because of prematurity. In one case a miscarriage at 6 weeks of gestation occurred simultaneously with SHiP. No maternal or neonatal deaths were reported, despite a high rate of emergency caesarean sections at preterm age (54.5%, n = 6). In most events, a multidisciplinary approach, with a radiologist (n = 8) and/or surgeon (n = 8), was successfully used.

110 GA delivery (wk+d)/ Delivery Birthmode/ weight 39 CS 2984 g 28+5 CS g 1245 (NICU) - 35+5 CS g 2965 34+2 CS g 2290 n.a. 40+5 VE 4035 g Estimated blood loss (mL) 3000 1100 1000 n.a. 600 2000 n.a. TM Treatment Treatment bleeding Suture- ligation & TachoSil® Resection & compression surgical gauzes Tissucol & Surgicel® n.a. Coagulation Suture- ligation & Spongostan n.a. Location lesions [Figure 1] veins Varicose posterior uterine wall Descending colon Rectosigmoid Near l. ovary L. uterosacral lig. n.a. lig. L. uterosacral L. uterovesical lig. L. uterovesical lig. n.a.

6 Intervention LS converted (midline LT to incision) (midline LT incision) (midline LT incision) Expectant management (midline LT incision) LS converted (midline LT to incision) Expectant management ­ Abdominal pain Haemoglobin level low ­ US: free peritoneal fluid Abdominal pain low level Haemoglobin US: free peritoneal fluid Abdominal pain US: free peritoneal fluid Abdominal pain low level Haemoglobin US: free peritoneal fluid Abdominal pain US: free peritoneal fluid Abdominal pain low level Haemoglobin Collapse Abdominal pain low level Haemoglobin freeCTA: peritoneal fluid bleeding) (non-active

Symptoms at presentation - - - ­ - - - ­ - ­ - ­ - - ­ - ­ - - ­ - - ­ - ­ - ­ - ­ - ART IVF IVF ­ - ­ ­ - ­ - - GA present. (wk+d) 19+3 28 23+2 24+3 34+2 pp+12 40+5 (labour) Endometriosis prior to pregnancy (rASRM stage) (IV)Yes (IV)*Yes (IV)Yes “ No No* (IV)Yes - Clinical summary cases of Age (y) Parity (G, P) 38 G3P0 35 G1P0 34 G3P2 “ “ 33 G1P0 “ G1P1 37 G4P1 Case Case (No.) I II III (RS) IV (RS) V Table 1

111 Chapter 6 GA delivery (wk+d)/ Delivery Birthmode/ weight n.a. 32 + 2 CS 2265 g (NICU) 6+0 D&C n.a. 37+6 CS 3145 g 37 CS 2940 g Estimated blood loss (mL) 3000 3500 2000 100 2000 Treatment Treatment bleeding Suture-ligation, adnexal extirpation & TachoSil® Suture- ligation Suture- ligation & Floseal® No treatment Suture- ligation & TachoSil® Location lesions [Figure 1] L. broad lig. / L. uterine vessels R. broad lig. / R. uterine vein R. broad lig. / R. uterine vein Posterior uterine wall; two haematomas expanding to both broad ligaments L. uterosacral lig. Intervention LS converted LT to (Pfannenstiel incision) (extended LT midline incision) LS converted (midline LT to incision) LT (Pfannenstiel incision) LS converted (midline LT to incision) Abdominal pain Nausea, vomiting US/MRI: free peritoneal fluid Abdominal pain US: free peritoneal fluid Abdominal pain low level Haemoglobin US: free peritoneal fluid Irregular contractions, abdominalincreasing pain - Nausea, vomiting Fetal distress Abdominal pain Nausea, vomiting low level Haemoglobin US/MRI: free peritoneal fluid

Symptoms at presentation ­ - ­ - ­ ------­ - - ART ­ - IVF IVF IVF - GA present. (wk+d) pp+30 32+2 6+0 37+6 (labour) 21 Endometriosis prior to pregnancy (rASRM stage) “ (IV)Yes (IV)Yes (IV)Yes (unknown) Yes - Clinical summary cases of (continued) Age (y) Parity (G, P) “ G4P2 33 G2P0 36 G3P1 28 G1P0 37 G5P2 Table 1 Case (No.) (RS) VI (RS) VII VIII

112

unit; care wk = week; tomography lig. = ligament; GA delivery (wk+d)/ Delivery Birthmode/ weight 33+5 CS 2400 g (NICU) 37 + 4 CS 3045 g (NICU) 30+1 CS g 1620 (NICU) intensive L. = left; extraction;

Estimated blood loss (mL) 3000 2500 1750 neonatal CTA = computed to fertilisation; VE = vacuum section; vitro Treatment Treatment bleeding Suture- ligation Coagulation & suture-ligation Suture- ligation IVF = in NICU = admission examination; age; CS = caesarean applicable; Location lesions [Figure 1] Posterior surface r. broad lig. / r. vein uterine Adhesion posterior uterine wall R. broad lig. R. round lig. L. uterosacral lig. Peritoneum bladder; multiple minor bleeding Medicine; US = ultrasound GA = gestational n.a. = not

SHiP; 6 Intervention LT (Pfannenstiel incision) LT (Pfannenstiel incision) (midline LT incision) g = gram; Reproductive for mL = millilitres; RS = recurrent Society management; imaging; R. = right; American Abdominal pain Signs hypovolemic of shock Fetal distress Abdominal pain Signs hypovolemic of shock Fetal distress Abdominal pain - Nausea, vomiting low level Haemoglobin Fetal distress US: free peritoneal fluid

Symptoms at presentation ------resonance EM = expectant ART - - IVF rASRM = revised curettage; and MRI = magnetic GA present. (wk+d) 33+5 37+4 (labour) 30+1 rmed postoperatively histological by examination. present. = presentation; fi techniques; D&C = dilation LT = laparotomy; Endometriosis prior to pregnancy (rASRM stage) No* No** (IV)*Yes reproductive pp = postpartum; d = day; - Clinical summary cases of (continued) Age (y) Parity (G, P) 31 G2P0 27 G1P0 37 G2P0 Table 1 Case (No.) IX X XI ART = assisted angiography; LS = laparoscopy; no. = number; y = years. *Presence endometriosis of con **Endometriosis diagnosed postoperatively using MRI

113 Chapter 6

Figure 1 - Map of the bleeding locations

I-XI = case number; L = Left; R = right

DISCUSSION

MAIN FINDINGS This case note review reports on 15 events of SHiP in 11 women. Important new findings are (1) absence of SHiP induced fetomaternal or perinatal mortality, (2) increased value of imaging as a diagnostic tool and (3) recurrence of SHiP within the same or a subsequent pregnancy.

SHIP AND ENDOMETRIOSIS In all of our reported cases, endometriosis was present and its involvement likely in the aetiology of SHiP. The suspicion that endometriosis is a possible risk factor for SHiP, was first suggested by Inoue et al. in 1992 [12]. They explained the involvement of endometriosis in SHiP by two mechanisms: (1) utero-ovarian vessels are more friable due to chronic inflammations associated with endometriosis and (2) resultant pelvic adhesions due to endometriosis in combination with enlargement of the uterus during pregnancy can place these vessels under greater tension, increasing the risk of rupture and bleeding [12]. On the other hand, the role of stretch in the pathogenesis of SHiP is questionable, as twin pregnancies or pelvic adhesions as a result of a previous abdominal operation or infection are not identified as risk factors for SHiP.

114 In addition, it has been shown that direct bleeding of endometriotic lesions may cause a haemoperitoneum [13]. During pregnancy, endometriotic lesions become decidualized and therefore enlarge during the first trimester. Later in pregnancy these lesions can shrink, probably due to decidual necrosis and involution [14]. Because decidualised endometrium is dependent upon sustained progesterone signalling, failing progesterone levels or devascularisation can cause a weakening of the tissue. In endometriotic tissue, characterised by dysregulation of gene expression leading to progesterone resistance [15,16], ‘functional’ progesterone withdrawal can lead to necrosis of decidualised foci of endometriosis resulting in (gastrointestinal) perforation and bleeding of unpredictable severity [6,17-20].

Brosens et al. [6] showed previously that SHiP-associated adverse pregnancy outcomes (including perinatal mortality and severe perinatal morbidity) were more frequent in women diagnosed with endometriosis, although an apparent relationship with the stage of endometriosis could not be found. Further research to examine the exact role of decidualised endometriosis in the aetiology of SHiP, and the associated vascular changes, is warranted and might be helpful in identifying women with an increased risk of developing (severe) SHiP.

SYMPTOMS AND DIAGNOSIS 6 It is difficult to identify SHiP as a clinical entity, as it is usually related to a non- specific presentation. Therefore numerous differential diagnoses (acute appendicitis; perforated gastric ulcer; gall- or bladder stones; preterm birth; HELLP syndrome- associated liver rupture; uterine rupture; placental abruption or ruptured vasculature of spleen or liver) are considered [21]. Until recently, imaging failed to show to be of value in diagnosing SHiP [6]. In the third trimester of pregnancy, adequate imaging, especially by transvaginal ultrasound, can be difficult due to the position of the uterus and the inability to get an overview of the abdominal cavity. However, in our series, imaging by abdominal ultrasound or MRI proved to be a good diagnostic tool when free peritoneal fluid was detected. Observations of intra-abdominal fluid collections can enhance the suspicion of a haemoperitoneum, although the exact origin and quantity of the bleeding usually remains unknown until surgery. Therefore, the diagnosis is rarely made preoperatively.

TREATMENT Surgical treatment of SHiP can be challenging, especially as SHiP mostly occurs during the second half of pregnancy. Laparoscopic exploration can be complicated due to the enlarged uterus and therefore bleeding sites, frequently situated on the posterior side of the uterus or surrounding ligaments, can be difficult to reach. When SHiP occurs in the second or third trimester, sometimes even a caesarean delivery has to be performed to be able to achieve haemostasis. There is only one case in the literature in which laparoscopic intervention during pregnancy (at 15 weeks of gestation) was

115 Chapter 6 successful without conversion to a laparotomy [22]. When considering expectant management, the possibility that recovery can be complicated by development of infected haematomas (case no. XI) or recurrence of SHiP (case no. V) must be taken into account. However, successful surgical intervention does not rule out recurrence of SHiP (case nos III, IV, VI).

RECURRENCE OF SHIP To our knowledge, this is the first time recurrence of SHiP, in the same (case nos III, IV, V) or a subsequent pregnancy (case no. VI), has been reported. However, because of expectant management in two of these cases (case nos III, V), recurrence could not be confirmed surgically. Nevertheless, there was a high suspicion of SHiP because of the clinical presentation and the decline in haemoglobin level. In addition, as recurrences of SHiP occurred in women diagnosed with endometriosis, it is tempting to speculate that the proposed aetiological mechanisms of SHiP are involved in this phenomenon as well, although numbers are too small and supporting evidence is lacking to draw firm conclusions.

MATERNAL AND PERINATAL OUTCOME SHiP is associated with adverse pregnancy outcomes for both mother and child. It is therefore remarkable that no neonatal deaths occurred in any of our cases, despite a high percentage (54.5%) of preterm births. Besides a possible risk of publication bias in earlier reports (there is a greater likelihood of SHiP cases to be submitted for publication with adverse maternal or perinatal outcome), increased awareness of SHiP, improved diagnostic value of imaging and adequate intervention, may also have contributed to the observed favourable perinatal outcomes. This is also illustrated in our series by three cases (case nos I, III, VIII) that showed a successful continuation of pregnancy after management of SHiP at 19–24 weeks of gestation. However, as shown by Brouckaert et al., successful management of SHiP early in pregnancy is not always feasible. They reported an excessive haemoperitoneum in an endometriosis patient at 17 weeks of gestation with bleeding at multiple sites, necessitating a hysterectomy with the fetus in situ [23].

STRENGTHS AND LIMITATIONS To further improve the outcome of pregnancies complicated by SHiP, creating awareness and gaining a growing knowledge are advocated. Because of the rarity of SHiP, a retrospective study design was necessary. With the collaboration of the members of the Dutch Working Group on Endometriosis, a comprehensive network of Dutch gynaecologists could be reached and the largest ever original case series concerning this topic was compiled. As cases were not systematically gathered, there is a possibility that suitable cases remained unreported in this review. Therefore an exact incidence number cannot be given and results have to be interpreted with caution.

116 INTERPRETATION AND IMPLICATIONS FOR CLINICAL PRACTICE AND RE- SEARCH This case note review demonstrates some important issues for the recognition and clinical approach of SHiP. As the number of pregnant women with endometriosis is increasing, it is important to emphasize the association of SHiP and endometriosis. However, until the exact incidence of SHiP is known and preventive measures are available, appropriate counselling of pregnant women with endometriosis remains difficult. An international registration network is warranted and currently running (INOSS; International Network of Obstetric Survey Systems) to record cases of SHiP in a prospective way (including data from the UK and the Netherlands) [24–26]. This network will allow us to give incidence numbers and acquire more insight into this complication of pregnancy.

CONCLUSION

It seemed that adequate multidisciplinary intervention resulted in favourable fetomaternal and perinatal outcomes, despite a high percentage of preterm births in this case series. To further improve the outcomes of SHiP, growing awareness of this serious complication of pregnancy is advocated, especially in women with 6 endometriosis.

117 Chapter 6

REFERENCES

1. Ginsburg KA, Valdes C, Schnider G. Spontaneous utero-ovarian vessel rupture during pregnancy: three case reports and a review of the literature. Obstet Gynecol. 1987;69:474–476. 2. Brosens I, Brosens JJ, Fusi L, Al-Sabbagh M, Kuroda K, Benagiano G. Risks of adverse pregnancy outcome in endometriosis. Fertil Steril. 2012;98:30–35. 3. Masouridou S, Mamopoulos A, Mavromdatidis G, Karagiannis V. Endometriosis and perinatal outcome - a systematic review of the literature. Curr Women’s Health Rev. 2012;8:121–130. 4. Williams JW. Intrapelvic hematoma following labor not associated with lesions of uterus. Am J Obstet. 1904;50:442–455. 5. Hodgkinson CP, Christenson RC. Hemorrhage from ruptured uteroovarian veins during pregnancy: report of three cases and review of the literature. Am J Obstet Gynecol. 1950;59:1112–1117. 6. Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril. 2009;92:1243–1245. 7. Passos F, Calhaz-Jorge C, Graca LM. Endometriosis is a possible risk factor for spontaneous hemoperitoneum in the third trimester of pregnancy. Fertil Steril. 2008;89:251–252. 8. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235–258. 9. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril. 2009;92:68–74. 10. Gruppo Italiano per lo Studio dell’ Endometriosi. Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Hum Reprod. 1994;9:1158–1162. 11. Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod. 1991;6:544–549. 12. Inoue T, Moriwaki T, Niki I. Endometriosis and spontaneous rupture of utero-ovarian vessels during pregnancy. Lancet. 1992;340:240–241. 13. Katorza E, Soriano D, Stockheim D, Mashiach R, Zolti M, Seidman DS, et al. Severe intraabdominal bleeding caused by endometriotic lesions during the third trimester of pregnancy. Am J Obstet Gynecol. 2007;197:501. 14. McArthur JW, Ulfelder H. The effect of pregnancy upon endometriosis. Obstet Gynecol Surv. 1965;20:709–733. 15. Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814–3826. 16. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19:406–418. 17. Brosens JJ, Gellersen B. Death or survival—progesterone-dependent cell fate decisions in the human endometrial stroma. J Mol Endocrinol. 2006;36:389–398. 18. Clement PB. Perforation of the sigmoid colon during pregnancy: arare complication of endometriosis. Case report. BJOG. 1977;84:548–550. 19. Gini PC, Chukudebelu WO, Onuigbo WI. Perforation of the appendix during pregnancy: a rare complication of endometriosis. Case report. BJOG. 1981;88:456–458.

118 20. Loverro G, Cormio G, Greco P, Altomare D, Putignano G, Selvagi L. Perforation of the sigmoid colon during pregnancy: a rare complication of endometriosis. J Gynecol Surg. 1999;15:155– 157. 21. Aziz U, Kulkarni A, Lazic D, Cullimore JE. Spontaneous rupture of the uterine vessels in pregnancy. Obstet Gynecol. 2004;103:1089–1091. 22. Pezzuto A, Pomini P, Steinkasserer M, Nardelli GB, Minelli L. Successful laparoscopic management of spontaneous hemoperitoneum at 15 weeks of pregnancy:case report and review of literature. J Minim Invasive Gynecol. 2009;16:792–794. 23. Brouckaert OM, Oostenveld E, Quartero H. Spontaneous hemoperitoneum and fetal demise in a nulliparous woman requiring hysterectomy with fetus in situ. Int J Gynaecol Obstet. 2010;110:273. 24. INOSS (Internet). Oxford: International Network of Obstetric Survey Systems (updated January 5th 2015). [www.npeu.ox.ac.uk/inoss]. Accessed June 14th 2016. 25. NethOSS (Internet). Utrecht: Netherlands Obstetric Surveillance System (updated April 1st 2016) [www.nethoss.nl]. Accessed June 14th 2016. 26. UKOSS (Internet). Oxford: UK Obstetric Surveillance System (updated January 16th 2016). [www. npeu.ox.ac.uk/ukoss]. Accessed June 14th 2016.

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CHAPTER 7

Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - a systematic review of the recent literature

Lier, M.C.I. Malik, R.F. Ket, J.C.F. Lambalk, C.B. Brosens, I.A. Mijatovic, V.

Eur J Obstet Gynecol Reprod Biol. 2017;219:57-65 Chapter 7

ABSTRACT

Spontaneous Hemoperitoneum in Pregnancy (SHiP), an unprovoked (nontraumatic) intraperitoneal bleeding in pregnancy (up to 42 days postpartum), is associated with serious adverse pregnancy outcomes. To evaluate the clinical consequences of SHiP and its association with endometriosis, a systematic review was conducted according to the PRISMA guidelines. PubMed, Embase.com and Thomson Reuters/Web of Science were searched for articles published since the latest review (August 2008) until September 2016.

After assessment for eligibility, forty-four articles were included in this systematic review, describing 59 cases of SHiP. Endometriosis was present in 33/59 cases (55.9%), most often diagnosed prior to pregnancy. An association between the severity of SHiP and the stage of endometriosis could not be found. In the majority of cases, SHiP occurred in the third trimester of pregnancy (30/59 cases (50.8%)); women presented with (sub)acute abdominal pain (56/59 cases (94.9%)), hypovolemic shock (28/59 cases (47.5%)) and/or a decreased level of hemoglobin (37/59 cases (62.7%)). Signs of fetal distress were observed in 24/59 cases (40.7%). Imaging confirmed free peritoneal fluid in (37/59 cases (62.7%)). At time of surgery active bleeding was revealed in 51/56 cases (91,1%), originating from endometriotic implants (11/51 cases (21.6%)), ruptured utero-ovarian vessels (29/51 cases (56.8%)), hemorrhagic nodules of decidualized cells (1/51 cases (2.0%)) or a combination (10/51 cases (19.6%)). Median amount of hemoperitoneum was 1600 mL (IQR 1000mL–2500 mL). From the 45/59 cases (76.3%) in which surgical interventions was carried out during pregnancy, 7/45 cases (15.6%) reported a successful continuation of pregnancy. 5/59 cases reported recurrence of SHiP (recurrence rate 8.5%). The perinatal mortality rate was 26.9% (18/67 fetus), one maternal death was reported (1/59 cases (1,7%)).

In conclusion, SHiP is a very serious complication of pregnancy, highly associated with adverse pregnancy outcomes and particularly relevant to women with endometriosis. Currently preventive measures are lacking, therefore increasing the awareness and recognition of SHiP is crucial to improve pregnancy outcomes.

122 INTRODUCTION

Spontaneous Hemoperitoneum in Pregnancy (SHiP), an unprovoked (nontraumatic) intraperitoneal bleeding in pregnancy (up to 42 days postpartum), is associated with serious adverse pregnancy outcomes [1,2]. SHiP was first described in the late 18th century [3] and since then high maternal mortality rates were reported (Williams 1904 [4], 18/32 cases (56%); Hodgkinson et al., 1950 [5], 37/75 cases (49%)). Rates were even higher in women giving birth [5]. In the last decades of the 20th century, the maternal mortality rate decreased significantly (Ginsburg et al., 1987 [1], 1/28 cases (4%); Brosens et al., 2009 [2], 0/25 cases (0%)), however perinatal mortality remained substantially high (10/28 cases (36%)) [2].

Although the exact etiology of SHiP is still unknown, endometriosis and the use of controlled ovarian hyperstimulation for artificial reproductive techniques (ART) seems to be contributive factors in the occurrence and severity of SHiP [2,6]. This is of importance, as ART is more frequently used in women diagnosed with endometriosis [7]. To gain a better insight in this potentially life-threatening complication of pregnancy and evaluate the clinical consequences, a systematic review of the recent literature published since the latest review of Brosens et al. in 2009 [2], was conducted.

Figure 1 - PRISMA flow diagram of the systematic literature search 7

123 Chapter 7

MATERIALS AND METHODS

A review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement (www.prisma-statement. org) [8]. For this paper, no approval of the institutional review board was required, since data were extracted from previously published reports.

SEARCH STRATEGY PubMed, Embase.com and Thomson Reuters/Web of Science were searched from August 2008 [2] (by MCIL and JCFK). PubMed and Embase.com up to September 15, 2016 and Thomson Reuters/Web of Science up to September 21, 2016. The following terms were used (including synonyms and closely related words) as index terms or free-text words: ‘haemoperitoneum’, ‘rupture’, ‘blood vessels’, ‘spontaneous’, ‘pregnancy’, ‘post-partum’, ‘labor’ and ‘endometriosis’. Duplicate articles were excluded. Reference lists of the retrieved publications were checked for relevant articles. The full search strategies for all databases can be found in the Supplementary Information (Appendix I).

ELIGIBILITY CRITERIA All case reports, case series, cross-sectional studies, prospective and retrospective cohort studies were considered for inclusion when they reported on spontaneous intra-abdominal bleedings in pregnancy, labor or within six weeks of the postpartum period. Only full-text reports were considered for inclusion, congress abstracts and poster-presentations were excluded. The search was limited to articles published in English. Articles reporting on cases of uterine ruptures, ectopic pregnancies, caesarean scar pregnancies, placental abnormalities, uterine abnormalities, artery (pseudo) aneurysm ruptures, trauma, hemolysis elevated liver enzymes and low platelets (HELLP) syndrome, pre-eclampsia, liver- or splenic rupture, malignancies, ruptured ovarian cysts and postpartum hemorrhage (PPH) were excluded (non-SHiP bleedings). Eligibility assessment of the retrieved articles was performed by two authors (MCIL and RFM) independently (not blinded). In case of doubt or disagreement regarding in- or exclusion, a third author (VM) was consulted to establish consensus. The flow diagram of the systematic literature search is shown in Figure 1.

DATA EXTRACTION Data extraction was performed by two authors independently (MCIL and RFM). Items that were included reported about general patient characteristics, clinical presentation, diagnostics, characteristics of the bleeding, treatment, perinatal and maternal outcomes. Authors were contacted in case additional information was required. Since only case reports and case-series were found, the quality of the obtained studies was not assessed.

124 STATISTICAL ANALYSIS Categorical variables were summarized by frequencies and percentages. Continuous variables were summarized by mean and standard deviation in case of normal distribution and median and inter-quartile range in case of a non-normal distribution. Categorical variables were compared between groups with and without endometriosis using chi-square test or Fisher’s exact test in case expected cell count was below 5 for at least one cell. Continuous variables were compared between groups using the independent samples t-test in case of a normal distribution and the Mann-Whitney test in case of non-normal distribution. Two sided p-values <0.05 were considered to indicate statistical significance. IBM Statistical Package for Social Sciences (SPSS) version 22.0 (IBM Corp., USA) was used for statistical analyses.

RESULTS

IDENTIFICATION OF THE LITERATURE The initial literature search identified 2132 records. Five additional records were identified by checking other sources and references lists. After removal of the duplicates, 1885 records were screened for eligibility; of which 126 records were selected for full-text assessment. From these records 82 articles were excluded for the following reasons; not written in English (n=13), no report of primary data (n=2), no availability of full-text article (in case of congress abstracts or poster-presentations, 7 n=13), reported on other causes of intra-abdominal bleeding (“non-SHiP bleedings” as mentioned in the in- and exclusion criteria, n=58).

Eventually forty-four articles were included in the analysis [9-52]. All articles that were eligible for inclusion were either case reports or case-series and described a total of 59 cases of SHiP. A summary of the cases is given in Table 1.

125 Chapter 7

Perinatal No No No No No No No Yes Yes Yes Yes mortality (2x) (2x)

Mode of CS CS CS CS CS CS

delivery Vag. Vag. Vag. Vag. Hyster ectomy

GA delivery - 17 24 37 35 29 30 38 40 33+2 (wk+d) 34+5 ------Biopsy (+/-) + + + +

HP (mL) 700 1700 3100 1500 1500 2490 3500 2000 3600 3000 3000 LT LT LT LT LT LT LT LT LT Intervention LS LS

GA SHiP 15 17 24 35 29 30 pp+2 33+2 pp+0 pp+0 (wk+d) 34+4 - - - - - + ART (+/-) + + + + +

Stage

(rASRM) n.a. n.a. n.a. n.a. Unknown Unknown Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV

Endome- triosis No No No No Yes, after Yes, pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy Yes, duringYes, Yes, prior Yes, to Yes, prior Yes, to prior Yes, to prior Yes, to prior Yes, to

Parity 0 0 2 0 2 0 0 1 0 0 1 31 35 28 29 39 38 33 33 34 40 Age (y) 43

Episode I * * II III

Ref. et al. [2008] [9] Gao et al. Summary cases of [2010] [15] [2010] [2010] [16] [2010] [2010] [17] [2010] [2009] [11] [2009] [12] [2009] [13] [2009] [10] [2009] [14] Wada et al. Brouckaert Brouckaert Bouet et al. Roche et al. Zhang et al. Bloom et al. Moreira et al. Pezzuto et al. 1 2 3 4 5 6 7 8 9 11 Case (no.) 10 Table 1 - Table

126 Perinatal No No No No No No No No Yes Yes mortality (2x)

Mode of CS CS CS CS CS CS CS n.a. delivery Vag. Vag.

GA delivery 42 29 36 33 40 >30 33+2 28+5 25+6 (wk+d) 40+6 ------Biopsy (+/-) +

HP (mL) 850 900 1000 1000 2500 2000 2000 LT Intervention LT LT LT LT LT LT LT LT Autopsy

GA SHiP 25 29 36 33 (L) >30 27+4 33+2 28+5 pp+0 (wk+d) 40+6 ------ART (+/-) + +

Stage n.a. (rASRM) n.a. n.a. n.a. n.a. 7 Unknown Unknown Unknown Severe: III/IV Severe: III/IV

Endome- No triosis No No No No pregnancy pregnancy pregnancy pregnancy pregnancy Yes, duringYes, duringYes, Yes, prior Yes, to prior Yes, to prior Yes, to

Parity 1 2 0 0 0 1 0 0 0 0 25 21 26 31 37 28 29 Age (y) 33 33 33

Episode I * II III IV

Ref. et al. et al. Kapila Kim et al. Summary cases (continued) of [2011] [24] [2011] [2011] [23] [2011] [2010] [21] [2010] [2010] [18] [2010] [2010] [20][2010] [2010] [22][2010] Grunewald Grunewald [2009] [19] Shahnewaj Giulini et al. Nakaya et al. Huisman et al. Case (no.) 15 19 12 17 14 16 13 18 21 20 Table 1 - Table

127 Chapter 7

Perinatal No No No No No No No No Yes Yes Yes mortality (2x) (2x)

Mode of CS CS CS CS CS CS CS CS

delivery Vag. Vag. Vag.

GA delivery 24 37 37 35 28 29 32 38 38 38 (wk+d) 40 ------Biopsy (+/-) + + + +

HP (mL) 400 1100 1500 1500 1000 2500 2500 3500 2000 3000

Intervention LT LT LT LT LT LT LT LT LT LT EM

GA SHiP 24 37 35 28 29 29 32 38 38

(wk+d) pp+0 pp+0 ------ART (+/-) +

Stage I/II n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.

(rASRM) Mild: Severe: III/IV Severe: III/IV

Endome- triosis No No No No No No No No Yes, after Yes, pregnancy pregnancy pregnancy Yes, duringYes, duringYes,

Parity 0 4 0 0 1 2 0 0 0 0 0 24 25 26 31 37 37 32 30 30 Age (y) 33 33

Episode * *

Ref. Fan et al. Summary cases (continued) of [2011] [25] [2011] [2012] [26] [2012] [2012] [27] [2012] Maya et al [2012] [29] [2012] [2013] [35] [2013] [2012] [28] [2012] [2013] [32] [2013] [2012] [33][2012] [2012] [30][2012] Al Qahtani [2013] [34][2013] Munir et al. Doger et al. Duhan et al. al. [2013] [31] al. [2013] Kondoh et al. et Kondoh Boztosun et al. De Vincenzo et Nguessan et al. et Nguessan Williamson et al. Case (no.) 31 26 25 29 24 27 32 28 30 23 22 Table 1 - Table

128 Perinatal No No No No No No No No No Yes mortality (2x)

Mode of CS CS CS CS CS CS CS CS CS

delivery Vag.

GA delivery 37 37 29 32 32 30 33 34 22+2 (wk+d) 38+6 ------Biopsy (+/-) +

HP (mL) 200 1500 1500 1500 1500 1300 2500 2200 2000 LT LT LT LT LT LT LT LT LT Intervention LS

GA SHiP 37 29 32 32 32 30 34 pp+7 21+6

(wk+d) 37 (L) ------ART (+/-) +

Stage I/II

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 7

(rASRM) Mild: Severe: III/IV

Endome- triosis No No No No Unknown Unknown Unknown Unknown pregnancy pregnancy Yes, prior Yes, to Yes, prior Yes, to

Parity 0 1 0 0 1 1 1 0 2 2 24 24 31 37 35 35 32 30 Age (y) 33 33

Episode *

Ref. et al. Shi et al. Lim et al. Summary cases (continued) of [2014] [41] [2014] [2015] [42] [2015] [2013] [37] [2013] [2015] [45][2015] [2014] [36][2014] [2014] [39][2014] [2015] [44][2015] [2014] [40][2014] Black et al. Kekhashan Kekhashan al. [2015] [43]al. [2015] al. [38] [2014] Fatnassi et al. Sreedhar et al. Diaz-Murillo et Aggarwal et al. Cozzolino et al. Farahbakhsh et Case (no.) 41 42 35 36 37 39 38 33 34 40 Table 1 - Table

129 Chapter 7

Perinatal No No No No No No No Yes Yes Yes mortality (2x)

Mode of CS CS CS CS CS CS CS CS CS

delivery D&C

GA delivery 41 29 39 38 22 16+5 28+3 34+2 28+5 (wk+d) 35+5 ------+ Biopsy (+/-) + +

HP (mL) ? n.a. 850 600 600/ 1500 1000 2000 3000 3000 1000/ 3000/ LT Intervention LT LT LT LT LT LT/ LT/ EM / LT LS --> LT LS --> LT LS --> LT

GA SHiP 28 29 38 16/ 19+3 21+6 16+5 24+3 28+2

(wk+d) 41 (L) 23+2/ 34+2/ pp+12 ------+ ART (+/-) + +

Stage

(rASRM) n.a. Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV

Endome- triosis Unknown pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy Yes, duringYes, duringYes, Yes, prior Yes, to Yes, prior Yes, to prior Yes, to prior Yes, to prior Yes, to prior Yes, to prior Yes, to

Parity 0 0 0 0 0 0 0 0 2 0 25 25 26 31 27 35 38 22 33 Age (y) 34

Episode * 2nd 2nd 2nd 1st/ 1st/ 1st/ I II II III IV

Ref. Lier et al. Lier et al. Lier et al. Lier et al. Loh et al. Summary cases (continued) of [2016] [51] [2016] [2015] [47] [2015] [2016] [50][2016] [2015] [46][2015] [2015] [48][2015] [2017] (52) [2017] (52) [2017] (52) [2017] (52) [2017] Zhang et al. Mandal et al. Ploteau et al. al. [2016] [49] al. [2016] Petresin et al. Stochino Loi et Case (no.) 47 51 49 52 50 45 46 48 43 44 Table 1 - Table

130

Perinatal and No No No No No No Yes mortality No/

Mode of no. = number; CS CS CS CS CS CS/ Vag. delivery D&C D&C = dilation

GA delivery 37 6+0 30+1 37+4 37+6 33+5 (wk+d) 40+5 32+2/ d = day; mort. = mortality; - - - - - Biopsy (+/-) + + section;

HP (mL) 100 n.a./ 1250 2500 2000 2000 3000 3000 3500/ mL = milliliters; CS = caesarean Intervention LT LT LT LT LT/ EM/ LS --> LT LS --> LT LS --> LT

GA SHiP Medicine; 21 (L) (L) (L)/ LT = laparotomy; 6+0 30+1 37+4 37+6 33+5 (wk+d) 40+5 32+2/ pp+30 - - - - + + +

ART (+/-) +/ Reproductive

Stage for (rASRM) LS = laparoscopy; 7 Unknown Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Severe: III/IV Society (L)= labor;

Endome- American triosis Yes, after Yes, pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy pregnancy Yes, duringYes, Yes, prior Yes, to Yes, prior Yes, to prior Yes, to prior Yes, to prior Yes, to 1 1 0 2 0 0 0

Parity 0/ rASRM = revised HP = hemoperitoneum; 31 27 37 37 37 28 Age (y) 36 33/

Episode 2nd 2nd 1st/ 1st/ techniques; management; X V XI IX VI VII VIII

Ref. reproductive EM = expectant Lier et al. Lier et al. Lier et al. Lier et al. Lier et al. Lier et al. Lier et al. Summary cases (continued) of [2017] (52) [2017] (52) [2017] (52) [2017] (52) [2017] (52) [2017] (52) [2017] [2017] (52) [2017]

Case (no.) 59 55 56 57 58 53 54 Table 1 - Table ART = assisted curettage; n.a. = not applicable; pp = postpartum; = reference; ref. vag. = vaginal delivery; wk = week; y = years. * = twin pregnancy.

131 Chapter 7

PATIENT CHARACTERISTICS Nulliparous women represented 40/59 cases (67.8%), 7/59 (11.9%) being twin pregnancies. 16/59 pregnancies (27.1%) were conceived after ART. Mean age was 31.5 (SD ±4.7). Endometriosis was present in 33/59 cases (55.9%; 6.1% rASRM stage I-II; 75.7% rASRM stage III-IV; 18.2% rASRM stage unknown); the majority of these women 22/33 cases (66.7%) were known to have surgically confirmed endometriosis, prior to pregnancy.

CLINICAL PRESENTATION & DIAGNOSTICS The onset of SHiP varied from 6 weeks of gestation up to 30 days postpartum, in the majority of cases SHiP occurred in the third trimester of pregnancy (30/59 cases (50.8%)). Women presented with (sub)acute abdominal or flank pain (56/59 cases (94.9%)) in combination with signs of hypovolemic shock (28/59 cases (47.5%)) and/ or a decreased level of hemoglobin (37/59 cases (62.7%)). Signs of fetal distress (abnormal or absent fetal cardiac activity) were observed in 24/59 cases (40.7%). Free peritoneal fluid was confirmed by imaging modalities in 37/59 cases (62.7%); most frequently visualized by ultrasound sonography (US; 33/37 cases (89.2%)). Placental abruption or uterine rupture were often mentioned as differential diagnosis prior to intervention.

INTERVENTION Surgical intervention was performed in 56/59 cases (94.9%); carried out for maternal reasons (39/56 cases (69.6%)), fetal distress (2/56 cases (3.6%)) or a combination of both (15/56 cases (26.8%)). In one case a hemoperitoneum was confirmed on autopsy (1/59 cases (1.7%)). In two cases expectant management was chosen (2/59 cases (3.4%)). At the time of surgery active bleeding was revealed in 51/56 cases (91.1%); originating from endometriotic implants (11/51 cases (21.6%)), ruptured utero-ovarian vessels (29/51 cases (56.8%)), hemorrhagic nodules of decidualized cells (1/51 cases (2.0%)) or a combination of these (10/51 cases (19.6%)). Bleeding sites were most often situated on the posterior surface of the uterus or the utero- ovarian vessels located in the parametrium [Figure 2]. In 15/56 cases (26.8%) a biopsy was taken during the surgical intervention; histological reports described signs of decidualized endometriosis (10/15 biopsies (66.7%)), deciduosis (2/15 biopsies (13.3%)); endometriosis (2/15 biopsies (13.3%)) or hemorrhagic infiltration (1/15 biopsies (6.7%)) in the specimens. The median amount of hemoperitoneum was 1600 mL (IQR 1000mL–2500 mL). A laparotomy was the initial intervention in 50/59 cases (84.7%). In 6/59 cases (10.2%) a laparoscopy was performed, although in half of these cases conversion to a laparotomy was needed due to blurred vision or the inability to reach the bleeding site. Of the cases in which a laparoscopic intervention was successful, one was carried out in the early stage of pregnancy (15 weeks of gestation), the other two in the postpartum period. Suture ligation was most frequently applied to achieve hemostasis, a hysterectomy had to be performed in 4/59 cases (6.8%).

132 An association between the severity of the bleeding and the stage of endometriosis could not be found (p = 0.43).

Figure 2 - Map of the bleeding sites

7

In five cases no bleeding points could be identified

MATERNAL AND PERINATAL OUTCOMES From the 45/59 cases (76.3%) in which surgical interventions was carried out during pregnancy, seven cases reported a successful continuation of pregnancy (7/45 cases (15.6%); SHiP first presented between 15 and 32 weeks of gestation). In five of these cases (5/45 cases (11.1%)) pregnancy could continue beyond 37 weeks. Recurrence of SHiP was described in five cases (5/59 cases (8.5% recurrence rate)); all recurrences, except for one, were reported during the same pregnancy or postpartum period. Maternal death was reported once (1/59 cases (1.7%)): a 21 year old primigravida presented at 29 weeks of gestation with an acute pain in the abdomen and signs of hypovolemic shock; she was dead on arrival at the hospital [23]. 14/59 cases reported on fetal or neonatal death (including four twin pregnancies), resulting in a perinatal mortality rate of 26.9% (18/67 fetus). Severe neonatal morbidity was reported in 3/67 infants (4.5%); two infants were admitted to the neonatal intensive care unit (NICU) due to asphyxia and cerebral ischemia. One newborn showed signs of severe respiratory distress. Perinatal mortality and morbidity rates were similar between women with and without endometriosis, as shown in Table 2.

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Table 2 - SHiP characteristics endometriosis vs. no endometriosis

Endometriosis No endometriosis p-value (n=33) (n=26) Age (years) 32.5 (± 4.6) 30.2 (±4.9) 0.09 mean (standard deviation) Conceived after ART 13 (39.4%) 3 (11.5%) 0.017** number of cases (%) Singleton pregnancy 28 (84.8%) 24 (92.3%) 0.38 Twin pregnancy 5 (15.2%) 2 (7.7%) number of cases (%) Gestational age SHiP (weeks) 28.0 (21.0-33.0) 32.0 (29.0-35.5) 0.008** median (25th- 75th percentile) Gestational age delivery (weeks) 33.5 (28.3–37.8) 34.0 (30.0-37.5) 0.77 (median with 25th- 75th percentile) Preterm birth < 37 weeks 19 (57.6%) 16 (61.5%) 0.72 number of cases (%) Amount hemoperitoneum (mL) 2000 (1062.5–3000) 1500 (1000 – 2375) 0.15 median (25th- 75th percentile) Maternal mortality 0 (0%) 1 (3.8%) 0.44 number of cases (%) Perinatal mortality 10 (29.4%) (n=34)* 4 (15.4%) 0.20 number of cases (%) Severe perinatal morbidity 1 (2.9%) (n=34)* 2 (3.8%) 0.22 number of cases (%) Recurrence SHiP 5 (15.2%) 0 (0%) 0.06 number of cases (%)

ART = assisted reproductive techniques; mL = milliliters; n = number. * including second episode of SHiP (recurrence) in consecutive pregnancy (Lier et al. [52] Case VI). ** p-value = <0.05.

COMMENTS

In this systematic review we evaluated the clinical course and pregnancy outcomes of SHiP. This overview can be used as a guidance for medical decision making and preconception counseling of women with endometriosis and a future child wish. It should however be noticed that endometriosis-associated acute hemoperitoneum outside pregnancy has also been described in a few cases and presents with similar clinical signs [53].

134 SHIP AND ENDOMETRIOSIS Although it is believed that pregnancy has a favorable influence on endometriosis, women should also be informed about the possible obstetric and postpartum complications that can occur. In general, the negative influence of endometriosis on pregnancy outcomes is currently a growing area of concern. A recent literature review discussed the wide spectrum of negative obstetrical events possibly related to endometriosis and adenomyosis [54]. The left lateral predisposition that endometriotic implants show [55, 56] and the fact that bleeding sites of SHiP are more frequently found in the left lateral hemipelvis, is of supportive evidence for the association between SHiP and endometriosis. Despite the growing evidence that endometriosis is a causative factor in the development of SHiP, it is still not possible to determine which patients are at risk for developing SHiP and no evidence exists whether treatment of endometriosis or surgery prior to pregnancy may be a preventive measure to lower the risk of SHiP bleedings. Moreover, extensive surgery can also have negative consequences by further weakening of fragile intra-abdominal structures and adhesions formation; one case described a ruptured utero-ovarian vein probably as a late complication of laparoscopic resection of deep endometriosis prior to pregnancy [13].

CLINICAL PRESENTATION & DIAGNOSTICS Pregnant women presenting with (sub)acute abdominal or flank pain should be suspected of SHiP, which remains the major presenting symptom for women with and without endometriosis. Depending on the severity of the intraperitoneal bleeding, 7 the abdominal pain can be accompanied by signs of hypovolemic shock, decreased level of hemoglobin or signs of fetal distress. In both groups, imaging modalities seems to be of added value for the detection of hemorrhagic peritoneal fluid. Better equipment, training and experience of radiologists may have contributed to this improved detection. Especially ultrasound sonography is an easy first-line examination tool which can be helpful to quantify the amount and occasionally the origin of the bleeding, by which misdiagnosis can be avoided.

INTERVENTION Management of SHiP depends on the clinical presentation as a result of the extent of the intra-abdominal hemorrhage and the gestational age. A surgical approach is often unavoidable, but expectant management can be considered when signs of hypovolemic shock or fetal distress are absent, especially in the postpartum period. However, since spontaneous intra-abdominal hemorrhages in pregnancy are most frequently of venous origin [2] and therefore of substantial quantity, a laparotomy is commonly the first-choice treatment. Additionally, surgery gives the opportunity to establish the presence of endometriosis, in approximately 33% of the SHiP cases endometriosis was not diagnosed until pregnancy complications occurred. It is recommended to have a histological confirmation of endometriosis and take a biopsy from the bleeding lesions, since decidual changes of endometriotic tissue may impede the diagnosis [2,57,58].

135 Chapter 7

Successful treatment with uterine artery embolization (UAE) has only been described in cases of uterine artery aneurysms [59], but could theoretically also be applied (with caution) in cases of SHiP with an arterial origin. Expectant management, combined with fluid resuscitation, can be considered when women are hemodynamic stable without signs of fetal distress. However, recurrence of SHiP is noted and close monitoring is advised.

MATERNAL AND PERINATAL OUTCOMES Although in women with endometriosis, SHiP presented earlier in pregnancy, no significant differences in perinatal or maternal outcomes were observed between both groups. However, perinatal mortality and morbidity remains a major problem of SHiP and does not seem to improve over the last decades [1,2]. To improve the outcome it seems necessary to create further awareness, in order to facilitate timely recognition and diagnosis of SHiP. Recently several countries took the initiative to register the occurrence of SHiP in a prospective way, gathered in a multinational collaboration (INOSS) [60], with the aim to further understand this rare complication of pregnancy and get insight in the exact prevalence and recurrence rate of SHiP.

STRENGTH AND LIMITATIONS This review was systematically conducted according to the PRISMA guidelines [8], ensuring methodological quality. Since this systematic review consists of case reports mainly, publication bias can be involved. Especially a potential bias regarding cases of SHiP in pregnancies conceived after ART or in women diagnosed with endometriosis. Since no other studies were available, the use of case reports was inevitable. Despite the use of all available cases, the sample size remained insufficient to detect small differences between groups. However, with 59 unique cases of SHiP, this systematic review is the largest inventory of these cases in the literature.

CONCLUSIONS

SHiP is a very serious complication of pregnancy and highly associated with adverse pregnancy outcomes. In particularly perinatal mortality and morbidity remains a major problem of SHiP and has not improved over the last decades. Endometriosis is the major risk factor for the occurrence of SHiP. Since the number of pregnant women with endometriosis is increasing, it is important to acknowledge the link between SHiP and endometriosis. An association between the severity of SHiP and the stage of endometriosis could not be established. As preventive measures and evidence-based interventions are currently not available, increasing the awareness and recognition of SHiP is crucial to further improve pregnancy outcomes.

136 REFERENCES

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138 40. Shi Q, Zhou HG, Liu XR, Li JP. Spontaneous hemoperitoneum with intrahepatic cholestasis during the third trimester of pregnancy. Int J Gynecol Obstet. 2014 Dec;127(3):297-298. 41. Sreedhar S, Rajeswari KS, Sivasundari M. Surprise in pandora box: Spontaneous intra-abdominal hematoma in pregnancy. J SAFOG. 2014;6:171-172. 42. Cozzolino M, Corioni S, Maggio L, Sorbi F, Guaschino S, Fambrini M. Endometriosis-Related Hemoperitoneum in Pregnancy: A Diagnosis to Keep in Mind. Ochsner J. 2015;15:262-264. 43. Farahbakhsh F, Barati M, Moramezi B, Zamanpoor Z. Spontaneous Uterine Vessels Rupture in a Pregnant Woman: A Case Report. Jentashapir J Health Res. 2015;6:e28705. 44. Fatnassi R, Mkhinini I, Torki E, Ragmoun H, et al. Hemoperitoneum Caused by Spontaneous Uterine Varicose Vein Rupture in the Third Trimester of Pregnancy-A Case Report. Gynecol Obstet (Sunnyvale). 2015;5:291. 45. Kekhashan A, Sree S, Hassan KA. Spontaneous Rupture of Right Uterine Artery in a Pregnant Women: A Rare Entity. JEMDS. 2015;4:7684-7688. 46. Loh MJ, Wee JY, Teo SB. Endometriosis in a twin pregnancy leading to massive hemoperitoneum and intrauterine death: A case report. J Endometr Pelvic Pain Disord 2015;7:86-88. 47. Mandal D, Ray A, Goswami AK, Mandal A. Spontaneous Rupture of Uterine Varicose Vein at 38 Weeks of Pregnancy: A Rare Case Report. JEMDS. 2015;4:2403-2407. 48. Zhang Z, Lou J. Acute Hemoperitoneum after Administration of Prostaglandin E2 for Induction of Labour. Case Rep Obstet Gynecol. 2015;2015:659274. 49. Stochino Loi E, Darwish B, Abo C, Millischer-Bellaiche AE, Angioni S, Roman H. Recurrent Hemoperitoneum During Pregnancy in Large Deep Endometriosis Infiltrating the Parametrium. J Min Invasive Gynecol 2016;23:643-646. 50. Petresin J, Wolf J, Emir S, Müller A, Boosz AS. Endometriosis-associated Maternal Pregnancy Complications - Case Report and Literature Review. Geburtshilfe und Frauenheilkunde. 2016;76:902-905. 7 51. Ploteau S, Lopes P. Regarding “Recurrent Hemoperitoneum During Pregnancy in Large Deep Endometriosis Infiltrating the Parametrium”. J Minim Invasive Gynecol. 2016;23:1200-1201. 52. Lier MCI, Malik RF, van Waesberghe JHTM et al. Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series. BJOG. 2017;124:306-312. 53. Buggio L, Aimi G, Vercellini P. Hemoperitoneum following sexual intercourse in a woman with deep infiltrating endometriosis. Gynecol Obstet Invest. 2016;81:559–562. 54. Vigano P, Corti L, Berlanda N. Beyond infertility: obstetrical and postpartum complications associated with endometriosis and adenomyosis. Fertil Steril. 2015;104:802-812. 55. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol. 1986;67:335-338. 56. Al-Fozan, Tulandi T. Left lateral predisposition of endometriosis and endometrioma. Obstet Gynecol. 2003;101:164-166. 57. Aziz U, Kulkarni A, Lazic D, Cullimore JE. Spontaneous rupture of the uterine vessels in pregnancy. Obstetrics and Gynecology. 2004;103:1089-1091. 58. Lier MCI, Brosens IA, Mijatovic V, Habiba M, Benagiano G. Decidual bleeding as a cause of spontaneous hemoperitoneum in pregnancy and risk of preterm birth. Gynecol Obstet Invest. 2017;82:313–321. 59. Konishi T, Mori K, Uchikawa Y, et al. Spontaneous Hemoperitoneum in Pregnancy Treated with Transarterial Embolization of the Uterine Artery. Cardiovasc Intervent Radiol. 2016;39:132-136. 60. INOSS [Internet]. Oxford: International Network of Obstetric Survey Systems. [updated Jan 5th 2015; cited Jun 14th 2016]. Available from: Available from: https://www.npeu.ox.ac.uk/inoss

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SUPPLEMENTARY INFORMATION

Search strategy for PubMed (15 September 2016) [Mesh] = Medical subject headings (MeSH) [tiab] = words in title or abstract

Search Query Items found #9 #4 OR #6 OR #8 1,054 #8 #5 AND #7 524 #7 spontaneous*[tiab] 317,452 #6 #5 AND (“2008”[Date - Entrez] : “3000”[Date - Entrez]) 754 #5 #1 AND (#2 OR #3) 2270 #4 #1 AND #2 AND #3 48 #3 “Endometriosis”[Mesh] OR endometrio*[tiab] 27,770 #2 “Pregnancy”[Mesh] OR “Postpartum Period”[Mesh] OR “Pregnancy 948,828 Trimesters”[Mesh] OR pregnan*[tiab] OR labor[tiab] OR labors[tiab] OR labour[tiab] OR labours[tiab] OR parturit*[tiab] OR postpart*[tiab] OR trimester*[tiab] #1 “Hemoperitoneum”[Mesh] OR hemoperitone*[tiab] OR 32,413 haemoperitone*[tiab] OR ((“Rupture, Spontaneous”[Mesh] OR ruptur*[tiab]) AND (“Blood Vessels”[Mesh] OR veins[tiab] OR vein[tiab] OR vessel*[tiab] OR artery[tiab] OR arteries[tiab] OR microvessel*[tiab]))

Search strategy for Embase.com (15 September 2016) /exp = EMtree keyword with explosion :ab,ti = words in title or abstract

Search Query Items found #7 #4 OR #6 763 #6 #1 AND (#2 OR #3) AND #5 709 #5 spontaneous*:ab,ti 385,623 #4 #1 AND #2 AND #3 89 #3 ‘endometriosis’/exp OR endometrio*:ab,ti 41,163 #2 ‘pregnancy’/exp OR ‘puerperium’/exp OR pregnan*:ab,ti OR labor:ab,ti 943,019 OR labors:ab,ti OR labour:ab,ti OR labours:ab,ti OR parturit*:ab,ti OR postpart*:ab,ti OR trimester*:ab,ti #1 ‘hemoperitoneum’/exp OR hemoperitone*:ab,ti OR haemoperitone*:ab,ti 46,355 OR (‘rupture’/exp OR ruptur*:ab,ti AND (‘blood vessel’/exp OR veins:ab,ti OR vein:ab,ti OR vessel*:ab,ti OR artery:ab,ti OR arteries:ab,ti OR microvessel*:ab,ti))

140 Search strategy for Thomson Reuters/Web of Science (21 September 2016) Indexes: SCI-EXPANDED, SSCI, A&HCI, ESCI; Timespan: All years TOPIC = words in title, abstract or (author) keywords

Search Query Items found #8 #7 OR #4 315 #7 #6 AND #5 AND #1 302 #6 #3 OR #2 620,490 #5 TOPIC: (spontaneous*) 355,293 #4 #3 AND #2 AND #1 36 #3 TOPIC: (endometrio*) 23,601 #2 TOPIC: (pregnan* OR labor OR labors OR labour OR labours OR parturit* 599,289 OR postpart* OR trimester*) #1 TOPIC: (hemoperitone* OR haemoperitone* OR (ruptur* AND (veins OR 20,968 vein OR vessel* OR artery OR arteries OR microvessel*)))

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CHAPTER 8

Severe spontaneous hemoperitoneum in pregnancy may be linked to in vitro fertilization in patients with endometriosis: a systematic review

Brosens, I.A. Lier, M.C.I. Mijatovic, V. Habiba, M. Benagiano, G.

Fertil Steril. 2016;106:692-703 Chapter 8

ABSTRACT

OBJECTIVE To evaluate existing evidence of a possible association in women with endometriosis between controlled ovarian hyperstimulation plus embryo transfer (COH+ET) and the occurrence of spontaneous hemoperitoneum in pregnancy (SHiP).

DESIGN Comprehensive review.

SETTING Not applicable.

PATIENT(S) None.

INTERVENTION(S) An electronic literature search up to February 2016 was conducted using Scopus and PubMed.

MAIN OUTCOME MEASURE(S) The role of COH+ET in SHiP.

RESULT(S) Controlled ovarian hyperstimulation plus embryo transfer may increase the severity or incidence of the rare condition known as SHiP. An analysis of published cases shows that bleeding often occurs from multiple or diffuse sites, mainly situated in the posterior pelvic cavity, making it difficult to control without interfering with the pregnancy itself. Spontaneous hemoperitoneum in pregnancy is linked to adverse perinatal outcomes, including stillbirth, neonatal mortality and very low or low birth weight. In 14 cases a biopsy of the bleeding site was obtained and in all cases, even in the absence of visible endometriosis, decidualization was documented. At present, the relatively small number of cases published prevents firm conclusions, although they are highly suggestive of a link between COH+ET in women with endometriosis and the occurrence and seriousness of SHiP.

CONCLUSION(S) Spontaneous hemoperitoneum in pregnancy is a rare but potentially fatal complication for the pregnant woman and her unborn child. In vitro fertilization in women with severe endometriosis may be a risk factor for SHiP.

144 INTRODUCTION

It is well recognized that pregnancy can relieve endometriosis-related symptoms and may be curative. Pregnancy is therefore considered within the therapeutic options for endometriosis. Medical literature dating from the middle of the last century also included reference to pregnancy for the prevention of endometriosis [1]. Joseph Vincent Meigs [2] stated his belief that ‘‘avoidance of endometriosis through early marriage and frequent childbearing is the most important method of prophylaxis.’’ In line with this, the term ‘‘pseudo-pregnancy’’ was introduced during the 1960s in relation to the therapeutic use of progestin [3].

Endometriosis is a recognized cause of infertility but has only seldom been linked to pregnancy complications. Recent reports highlighted the rare yet life-threatening occurrence of spontaneous hemoperitoneum in pregnancy (SHiP). This dramatic complication has been associated with perinatal mortality and morbidity [4,5]. Doyle and Philips [6] were the first to describe the autopsy of a woman who died from SHiP and linked the bleeding to a small decidual peritoneal lesion on the lateral pelvic wall. O’Leary [7] reviewed pathology reports of cases of SHiP described between 1929 and 2006 and found two maternal deaths, three fetal deaths and two neonatal deaths in the 10 cases he identified. He described decidualization with no evidence of endometriosis in seven cases and decidualization in an endometriotic lesion in three cases. O’Leary [7] concluded that, although ectopic decidualization is usually no more than a pathologic curiosity, in rare cases it may be linked to feto-maternal mortality and morbidity. 8

A series of recent reports drew attention to a possible link between IVF carried out in women with endometriosis and SHiP. In one retrospective report, Katorza et al. [8] reviewed the clinical notes of 800 women attending an endometriosis center and identified three women who had intra-abdominal bleeding between 26 and 29 weeks’ gestation. All three women had IVF. Other case series of SHiP after IVF, mostly in women with endometriosis, have been published since [8–12]. In a series of 11 cases of SHiP in women with endometriosis, Lier et al. [9] documented six cases following IVF treatment. Two maternal deaths have recently been reported due to a delay in the diagnosis of SHiP [13,14]. Ueda et al. [15] reported abscess formation and rupture in 2 of 25 cases with endometriomas who underwent IVF. On the other hand, assisted reproductive technology was not linked to adverse pregnancy outcomes. This reflects the fact that SHiP is very rare. It has also been reported in singleton and twin pregnancies [16,17], although it may be more common in women with endometriosis who conceive after IVF. To test for a possible association, we undertook a literature review of reported cases of SHiP in women with and without endometriosis related to the use of IVF.

145 Chapter 8

MATERIALS AND METHODS

SEARCH STRATEGY A Scopus search, using the term ‘‘spontaneous hemoperitoneum in pregnancy,’’ produced a total of 474 publications, starting with the publication by Reid in 1945 [18]. The search was extended by mining the references for case reports, case series and reviews. After reading the abstracts and, if relevant, the full articles, a total of 57 case reports were identified. All cases with an established known cause explaining the hemoperitoneum were then excluded. This search was limited to articles published in English, French, or Spanish. For completion, a PubMed search was also carried out using the terms ‘‘hemoperitoneum’’ and ‘‘pregnancy,’’ yielding 859 articles. When the search was limited to the period 2007– 2016, it yielded 318 articles. A manual search of these articles was undertaken to exclude those dealing with ectopic pregnancy, pregnancy in a bicornuate horn, placenta accrete or percreta, uterine rupture, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, pre-eclampsia, ovarian hyperstimulation and hepatic or splenic rupture. This left 80 references; 55 of them contained the word ‘‘spontaneous’’ and 25 did not. Finally, all articles concerning endometriosis and/or IVF were selected. Because the purpose of this review is to examine occurrence of hemoperitoneum during pregnancy, reports of SHiP during labor or the postpartum period were excluded.

RESULTS

The aggregated search identified 45 articles, encompassing 64 case reports. These were divided into three groups on the basis of whether patients received assisted conception and the presence or absence of endometriosis. Group 1 included 24 cases of SHiP in women who underwent IVF. This group includes 22 cases in women who were diagnosed with endometriosis. Group 2 included 20 cases in women who conceived spontaneously and who had endometriosis. This group included all cases published since the first reported case of endometriosis and SHiP in 1992. Group 3 included 20 cases in women who had natural conception and who did not have endometriosis. In this group, in the absence of biopsies, the presence of ectopic deciduosis cannot be excluded. Because the first case of SHiP after IVF was published in 2007, we used the same year for including publications in group 3.

CLINICAL FEATURES Group 1 [Table 1] included 24 pregnancies following controlled ovarian hyperstimulation and embryo transfer (COH+ET). Women’s age ranged between 25 and 43 years. Nineteen women (79%) were nulliparous. Twenty-two women (92%) had severe, stage III or IV endometriosis. Group 2 [Table 2] included 16 cases with surgical diagnosis of endometriosis and 4 cases with no prior diagnosis of endometriosis, where the biopsy showed the presence of decidua, allowing a diagnosis of ectopic deciduosis,

146 as described by Kondoh et al. [36]. The age range of the group was between 25 and 37 years. Thirteen women (65%) were nulliparous. The stage of endometriosis varied from minimal to severe. Four women had ectopic deciduosis. Group 3 [Table 3] included 20 cases of SHiP with an age range of 21–40 years; eleven women (55%) were nulliparous. Women in this group did not have endometriosis at the time of laparotomy, although no biopsies were taken from the site of bleeding. It should be noted that in one case, deep endometriosis was diagnosed 4 years later by magnetic resonance imaging.

LOCALIZATION AND NUMBER OF BLEEDING SITES In group 1 SHiP occurred in 21 women (88%) during the second half of pregnancy and at 6, 17 and 19 weeks in the other 3 cases. In group 2, bleeding occurred between 21 and 37 weeks in all cases. In group 3, the bleeding occurred after 27 weeks in all cases. The mean duration of gestation at the time of bleeding was 28.6 weeks for group 1, 30.9 weeks for group 2 and 32.3 weeks for group 3. The difference between group 1 and 3 was statistically significant (P=.004). There were no statistically significant differences in the duration of gestation between group 2 and either group 1 (P=.29) or group 3 (P=.079) (unpaired t test). In the majority of cases bleeding was from the serosa of the posterior wall of the uterus, the broad ligaments or the utero-sacral ligaments, bleeding was recorded as venous at the site of varicosities. In some cases bleeding occurred at the site of a peritoneal tear, suggesting a two-step process whereby a hematoma forms in the loose areolar tissue of the parametrium before rupturing into the peritoneum. The bleeding site could not be identified in two cases in group 3.

Multiple (more than two) or diffuse bleeding points were observed in 16 cases (67%) 8 in group 1, in 3 cases (15%) in group 2, and 3 (15%) cases in group 3. The difference between group 1 and the two other groups was statistically significant (P=.0005). Among cases in which total blood loss was reported, the average amount of blood loss was higher in group 1 (2,720 mL) compared with group 2 (2,152 mL) and group 3 (1,805 mL), but the difference between the groups was not statistically significant. When the report included histopathology of bleeding sites (n=14), decidualization was confirmed in all cases.

PERINATAL AND MATERNAL OUTCOMES Adverse perinatal outcome included stillbirth, neonatal death, cerebral palsy, miscarriage and prematurity. Delayed transportation was considered a contributory factor in the one maternal death that occurred in group 3 [14]. In most cases delivery was by cesarean section. This was linked to extended laparotomy to allow access to the posterior aspect of the uterus and to the adnexa. Adverse maternal morbidities included the need for hysterectomy and adnexectomy. In most cases there was considerable blood loss requiring extensive transfusion of blood and blood products. The surgical challenge posed by this presentation is considerable, as demonstrated by detailed literature accounts [20,23].

147 Chapter 8 Outcome birthLive birthLive birthLive Miscarriage birthLive birthLive loss Fetal birthLive Birth weight (g) 2.984 1.245 2.265 - 3.145 1.620 - 3.200 Perinatal outcome Gestation age (wk) 19 28 32 6 37 30 17 40 hysterectomy ovariectomy nd st Surgical intervention Surgical wk,Laparotomy at 19 cesarean section at 38 wk Cesarean section Cesarean section Laparoscopy, surgical laparotomy, evacuation Cesarean section Cesarean section 1 2 fetus in situ Cesarean section Blood Blood loss (mL) 3.000 1.100 3.500 2.000 100 1.750 14.600 Large clots No. of bleeding sites M M M 1 M M D M Maternal outcome Maternal

nd episode) st Site of bleeding uterine Posterior varicosities Left ovary, bowel Right broad ligament varicosities Right broad ligament, right uterine artery Back uterus, of left and right broad ligament, bilateral hematoma ligament, broad Right round right ligament. Left uterosacral ligament, bladder. Right ovary (1 Broad ligament (2 episode) Douglas of Pouch adhesions Endometriosis stage Stage IV Stage IV Stage IV Stage IV Stage IV Stage IV Stage IV, endometrioma Severe endometriosis Para 0 0 0 1 0 0 0 0 Age (y) 38 35 33 36 28 37 33 29 – Details subjects of with a diagnosis endometriosis of who conceived through COH+ET Group 1 Year Author, [reference] Singleton pregnancies Lier et al., [9] 2016 Brouckaert et al., 2010 [19] Kim et al., 2010 [10] Table 1

148 Outcome birthLive birthLive birthLive loss Fetal birthLive Stillbirth, neonatal death Stillbirth, neonatal death birthLive Birth weight (g) 2.580 1.070 1.570 Not available 1.425 - - / 1.760 1.730 Perinatal outcome Gestation age (wk) 35 30 31 26 29 21 22 32 Surgical intervention Surgical Cesarean section Cesarean section Cesarean section of Termination pregnancy Adnexectomy Cesarean section Hysterotomy Left adnexectomy Cesarean section Cesarean section Blood Blood loss (mL) 1.700 1.500 Large clots 3.00 Small amount 3.500 2.200 400 No. of bleeding sites 1 M 2 M M M M 1 Maternal outcome Maternal 8 Site of bleeding ligament broad Right varicosities of wall Posterior varicosities uterus Right and left broad ligament varicosities Right broad ligament and adnexa Anterior and posterior wall of uterus of wall Posterior uterus, left fallopian tube Left tube fallopian Posterior uterus, of wall Utero-ovarian vein Endometriosis stage Stage II Surgically confirmed Stage III Severe endometriosis, endometrioma Severe endometriosis, endometrioma Stage IV, endometrioma Severe endometriosis No endometriosis Para 0 1 0 1 0 0 0 0 Age (y) 35 38 32 31 32 31 31 26 – Details subjects of with a diagnosis endometriosis of who conceived through COH+ET (continued) Table 1 Group 1 Year Author, [reference] Zhang et al., 2009 [11] Passos et al., 2008 [12] Katorza et al., 2007 [8] pregnancies Twin Loh et al., [16] 2015 Aggarwal et [17] al., 2014 Doger et al., [20] 2013

149 Chapter 8 Outcome birthLive birthLive birthLive Stillbirth birthLive Stillbirth birthLive birthLive Birth weight (g) / 1.190 890 / 2.715 2.340 / 2.190 2.300 - 1.830 / 1.740 - / 1.075 1.210 Not available Perinatal outcome Gestation age (wk) 27 37 33 29 32 33 28 33 Surgical intervention Surgical Cystectomy Cesarean section Cesarean section Cesarean section delivery andVaginal cesarean section Cesarean section Cesarean section Cesarean section Blood Blood loss (mL) 1.500 1.000 2.000 3.100 Large clots 3.000 2.000 4.000 No. of bleeding sites D 1 M 1 D M M 1 Maternal outcome Maternal Site of bleeding Left ovary of wall Posterior varicosities uterus of wall Posterior varicosities uterus of wall Posterior varicosities uterus of wall Posterior uterus, left broad ligament hematoma of wall Posterior uterus, right uterine artery of wall Posterior uterus varicosities, fossa ovarian of wall Posterior uterus Endometriosis stage Stage III, endometrioma No endometriosis Stage IV Stage III Stage III, endometrioma Stage IV Severe endometriosis Severe endometriosis, endometrioma Para 0 0 0 0 0 1 0 1 Age (y) 25 32 33 38 30 43 31 – Details subjects of with a diagnosis endometriosis of who conceived through COH+ET (continued) Table 1 Group 1 Year Author, [reference] Reif et al., [21] 2011 Andrés-Orós et al., 2010 [22] Kim et al., 2010 [10] Zhang et al., 2009 [ 11] Passos et al., 2008 [12] Roche et al., 2008 [23] Katorza et al., 2007 [8] etWu al., 2007 [24] D = diffuse; M = multiple

150 Outcome birthLive birthLive birthLive Stillbirth birthLive Stillbirth Neonatal death Birth weight (g) 2.965 2.290 2.940 - 1.390 - 3.700 Perinatal outcome Gestation age (wk) 35 34 37 16 29 24 41 Surgical Surgical intervention Laparotomy at 23 wk, cesarean section at 35 wk Cesarean section, laparotomy 2 wk postpartum Laparotomy at wk,21 cesarean section at 37 wk Laparotomy, termination of pregnancy Cesarean section, adnexectomy Cesarean section, resection bowel Forceps delivery, laparoscopy, laparotomy Blood loss loss Blood (mL) 1.100 600 2.000 3.000 1.500 2.500 Massive Maternal outcome Maternal No. of bleeding sites 1 2 1 1 2 1 1 8 Site of bleeding Left uterosacral ligament Uterovesical fold, left ligament uterosacral Left uterosacral ligament Left ligament, broad left uterine artery Right ovary, posterior surfaceuterine uterine Posterior surface, bowel, left uterine artery Left broad ligament, uterine artery Endometriosis stage Stage IV Yes Yes Deep infiltrating nodule Stage II Surgical confirmed Severe Para 2 0 2 0 1 0 0 Age (y) 34 33 37 26 33 33 31 – Details subjects of with a diagnosis endometriosis of deciduosis (or during pregnancy) who conceived naturally Group 2 Year Author, [reference] Endometriosis Lier et al., [9] 2016 Stochino et [25] al., 2016 Cozzolino et [26] al., 2015 De Vincenzo et al., 2013 [27] Girard et al., [28] 2012 Table 2

151 Chapter 8 Outcome Stillbirth birthLive birthLive birthLive birthLive birthLive Stillbirth Stillbirth birthLive Birth weight (g) 2.700 1.200 4.665 720 Not available 2.354 - - 1.416 Perinatal outcome Gestation age (wk) 37 28 42 25 40 37 31 20 29 Surgical Surgical intervention deliveryVaginal Cesarean section, excision tumor Laparotomy Cesarean section Vaginal delivery, hysterectomy Laparotomy implantation Ureter Adnexectomy Cesarean section Blood loss loss Blood (mL) Hematoma Massive 900 1.000 Clots 2.490 2.000 4.000 3.000 Maternal outcome Maternal No. of bleeding sites 1 1 1 M 2 1 1 1 1 Site of bleeding Left ligament broad hematoma wall, uterine Posterior left uterine artery uterosacral Right ligament 27 at wk wall uterine Posterior varicosities Subserosal vessel, Douglas of pouch adhesions wall uterine Posterior varicosities Right broad ligament, right uterine artery Left broad ligament, anterior uterine wall Anterior uterine wall, varicose veins Endometriosis stage Endometrioma Sigmoid endometriosis Stage I Surgical confirmed Stage II Stage IV Stage IV Surgical confirmed Severe Para 0 1 2 0 1 2 0 0 0 Age (y) 37 28 33 28 37 31 25 30 37 – Details subjects of with a diagnosis endometriosis of deciduosis (or during pregnancy) who conceived naturally (continued) Group 2 Year Author, [reference] Williamson et [29] al., 2011 et al., Tourette [30] 2011 et Grunewald [31] al., 2010 Kim et al., 2010 [10] Wada et al., 2009 [32] Chiodo et al., 2008 [33] Azis et al., 2004 [34] Inoue et al., 1992 [35] Table 2

152 Outcome birthLive birthLive Stillbirth Neonatal death Birth weight (g) 2.400 1.318 - 1.250 Perinatal outcome Gestation age (wk) 33 29 24 28 Surgical Surgical intervention Cesarean section Cesarean section Cesarean section Cesarean section Blood loss loss Blood (mL) 3.000 Large amount 700 4.000 Maternal outcome Maternal No. of bleeding sites 1 M 1 M 8 Site of bleeding Right broad ligament, vein uterine of wall Posterior omentum uterus, Left ligament broad artery uterine rent; of wall Posterior uterus veins Endometriosis stage No No No No Para 0 0 0 0 Age (y) 31 31 33 28 – Details subjects of with a diagnosis endometriosis of deciduosis (or during pregnancy) who conceived naturally (continued) Group 2 Year Author, [reference] Deciduosis Lier et al., [9] 2016 Kondoh et al., [36] 2012 Bouet et al., 2009 [37] Muzimoto et al., [38] 1996 Table 2 M = multiple

153 Chapter 8 Outcome birthLive birthLive birthLive birthLive birthLive birthLive birthLive birthLive birthLive birth live Twin Still birth Birth weight (g) 3.045 3.100 Not available 1.730 2.390 3.300 Not available 1.700 1.410 Not available 1.700 Perinatal outcome Gestation age (wk) 37 32 37 37 32 38 38 32 29 35 29 Surgical intervention Surgical Cesarean section Cesarean section Embolization, cesarean section Cesarean section Laparotomy Cesarean section Cesarean section Cesarean section Cesarean section Cesarean section Maternal death Blood Blood loss (mL) 2.500 1.300 Moderate 1.500 1.500 3.000 2.500 400 1.500 1.100 Large amount Maternal outcome Maternal No. of bleeding sites 1 1 M M 0 1 1 1 1 M 1 Site of bleeding posterior Adhesion wall uterus Left ligament broad varicosities of wall Posterior uterus, left broad varicosities ligament uterine Posterior Varicosities bleedingNo lesion Left utero-ovarian Ligament uterine Posterior Varicosities uterine Posterior Varicosities ligament broad Right Tear ligament broad Right Varicosities Left ligament broad Tear Endometriosis stage biopsy) (no Yes No No No No No No No No No No Para 0 2 0 1 1 2 4 0 1 0 0 Age (y) 27 35 35 24 33 32 37 27 36 33 21 – Details subjects of with no prior diagnosis endometriosis of who conceived naturally Group 3 Year Author, [reference] Lier et al., [9] 2016 Fatnassi et [39] al., 2015 Diaz-Murillo et al., 2014 [40] Lim et al., [41] 2014 Shi et al., [42] 2014 Munir et al., [43]2012 Al Quahtani et [44]al., 2012 Detriche et [45]al., 2012 Girard et al., [28] 2012 et Nguessan [46]al., 2013 Kapila et al., [14] 2011 Table 3 Table

154 Outcome birthLive still Twin birth birthLive birthLive birthLive birthLive birthLive birthLive birthLive Birth weight (g) 1.150 Not available 2.570 2.110 3.600 3.680 3.000 2.650 1.000 Perinatal outcome Gestation age (wk) 28 33 34 33 38 40 38 37 27 Surgical intervention Surgical Cesarean section Cesarean section Vaginal delivery, postpartum laparotomy Cesarean section Laparoscopy at 15wk, Cesarean Section at 38wk birth,Vaginal exploratory laparotomy Hemostatic sutures 22at wk Cesarean section Cesarean section Blood Blood loss (mL) 850 2.000 1.500 2.500- 3.000 3.600 3.000 2.500 700 800 Maternal outcome Maternal No. of bleeding sites 1 - 1 1 1 1 1 0 - 8 Site of bleeding ligament: broad Right superficialvein uterine Posterior varicosities Right and left broad artery uterine ligament, Left ligament broad varicosities Left ligament broad tear, uterine artery Left ligament, broad Bladder varicosities ligament, broad Right uterine artery No bleeding sites Posterior wall of uterus, uterine artery Endometriosis stage No No No No No No No No No Para 0 0 0 1 0 2 2 0 0 Age (y) 25 36 28 31 40 39 23 24 28 – Details subjects of with no prior diagnosis endometriosis of who conceived naturally (continued) Group 3 Year Author, [reference] Nakaya et al., [47] 2011 Andrés-Orós [22]et al., 2010 Bloom et al., [48]2010 Giulini et al., [49] 2010 Pezzuto et al., 2009 [50] Moreira et al., 2009 [51] Rosales et al., 2008 [52] Koifman et al., 2007 [53] Fiori et al., 2007 [54] Table 3 Table M = multiple

155 Chapter 8

DISCUSSION

PATHOPHYSIOLOGY OF SHIP There are a number of well-known causes of intraperitoneal bleeding during pregnancy. The most common during early pregnancy is a ruptured ectopic pregnancy or a ruptured hemorrhagic ovarian cyst.

Intraperitoneal bleeding is less common in late pregnancy, but obstetricians are well familiar with possible causes, namely uterine rupture, an abnormally invasive placentation and abruptio placentae leading to uteroplacental apoplexy (also known as Couvelaire uterus), a situation in which the retro placental blood infiltrates the uterine wall ending in the peritoneal cavity. HELLP syndrome complicating pregnancy has also been linked to bleeding from liver rupture. The literature also contains case reports of less frequently encountered causes of nontraumatic spontaneous intraperitoneal bleeding in pregnancy. Some of these relate to bleeding from nonreproductive organs, such as the splenic vein [55,56], splenic artery [57], visceral branches of abdominal aorta [58], or the suprarenal glands [57]. Bleeding has also been reported from hepatic rupture [59,60], liver hemangioma [61], or a ruptured gall bladder [62]. Of particular interest are reported cases in which there are features of decidualization in the bleeding lesions.

Rare cases have also been reported of bleeding during the postpartum period from the ovarian [63] or uterine arteries [13] and uterine veins [57,64,65].

Typically, women presenting with SHiP are mostly in the second half of pregnancy. More rarely, they may present during the first half of pregnancy or early in the postpartum period. They present with severe sudden onset of abdominal pain, systemic evidence of hypovolemia and collapse with no vaginal bleeding. The diagnosis is rarely made before exploratory laparotomy. Identifying and addressing the source of the severe bleeding is very challenging and often requires input from other surgical specialties. Bleeding from the reproductive tract vasculature often originated from the posterior aspect of the uterus or the broad ligament, which are difficult if not impossible to access without prior cesarean delivery. Bleeding can also be retroperitoneal. For the offspring the condition has been associated with a high rate of stillbirth and prematurity and for the mother with the need for hysterectomy, adnexectomy, or repeat laparotomy and has rarely proved fatal owing to the difficulty in ensuring timely response to bleeding and in view of the significant surgical challenge.

MAIN FINDINGS In this article we adopted the term COH+ET as proposed by Järvelä et al. [66] to refer to traditional ovarian stimulation IVF. To the best of our knowledge this is the first review that specifically examined the possible link between COH+ET and the occurrence of

156 SHiP in women with endometriosis. Although this conclusion seems warranted by the evidence collected, caution is required because the rarity of the condition forced us to rely on case reports with different degrees of accuracy. An important observation is the larger number of bleeding points observed in women with endometriosis undergoing COH+ET using traditional ovarian stimulation cycles. This is a point that warrants consideration.

Approximately one-third of all cases identified in the present search refer to women who underwent IVF. Only two (8%) of the cases with SHiP in the IVF group did not have endometriosis, with the majority having moderate or severe disease. The profile of reported cases suggests that COH+ET in women with endometriosis may increase the incidence or severity of SHiP. Several observed features seem to support the existence of an association: first, the presence of multiple or diffuse bleeding sites; second, the occurrence of decidualization in all cases that had a biopsy of the bleeding site; and third, the site of decidualization, which largely involved the parametrium and ovarian endometriomas. The common site of bleeding was in the posterior pelvic cavity, which is difficult to reach in the presence of advanced pregnancy without interfering with the pregnancy itself.

On the basis of pelvic inspection and biopsy, three clinical subgroups of SHiP can be distinguished: (1) ectopic deciduosis in women without endometriosis; (2) decidualized foci of endometriosis; and (3) diffuse decidualization in patients with SHiP linked to COH+ET. The severity of the presentation is reflected by adverse perinatal outcome, including stillbirth, neonatal mortality, very low birth weight, or low birth weight. 8

Although the paucity of reported cases in the group of women with IVF who did not have a diagnosis of endometriosis suggests that COH+ET is a risk factor for SHiP in the subgroup of women with moderate or severe endometriosis, their very limited absolute numbers necessitate a word of caution.

Thirty-eight of the cases identified in this review (59%) had endometriosis, which again suggests that endometriosis may to be linked to an increased incidence of SHiP. The group who underwent COH+ET and subsequently developed SHiP had a high incidence of advanced endometriosis, including a high incidence of endometrioma-related surgery. However, although endometriosis is well recognized as a cause of pelvic adhesions, which can cause severe limitation of uterine mobility as detected clinically or at the time of surgery, little is understood about how these adapt to pregnancy to allow uterine enlargement. The process can be envisaged to be associated with considerable stretch or breakdown, perhaps facilitated by softening in response to higher than usual circulating levels of Progestrone (P) during early pregnancy in women who underwent COH+ET [66]. It is also possible that a breakdown of adhesions and associated vasculature can occur within this process. The surgical difficulty in

157 Chapter 8 controlling the bleeding is further evidence of increased tissue susceptibility and the need for a judicious surgical approach. This must also be understood with reference to the hyperdynamic circulatory state and the extensive pelvic varicosities of pregnancy. One important argument against the role of stretch in the pathogenesis of SHiP is that there does not seem to be a higher number of reported cases in twin pregnancy.

The cases presented here illustrate the surgical challenge when attempting to control bleeding from multiple decidualized lesions. Decidualization has long been a recognized feature of the peritoneum during pregnancy and does not in itself indicate underlying endometriosis [67,68]. Yet the tissue can be friable to handle and attempts to control bleeding with suture material or diathermy may be futile, culminating in the need for excisional surgery and removal of the uterus or adnexa. The impact on affected women is considerable. Surgical access can also be difficult because bleeding is often from the posterior uterine wall or the posterior aspect of the broad ligament, which are difficult to access in a pregnant woman. It seems that most attempts to control bleeding while maintaining the pregnancy have been unsuccessful, and cases have been reported with recurrent bleeding necessitating hysterotomy and supracervical hysterectomy [16,19]. Therefore, in the presence of SHiP during the third trimester, consideration should be given to delivery by cesarean section at an early stage. One further difficulty is that the diagnosis of SHiP has been rarely made preoperatively, because imaging for intraperitoneal bleeding is very difficult in advanced pregnancy owing to the position of the uterus. It is unclear whether heightened attention to the existence of SHiP may enable a provisional diagnosis before surgery or the identification of less severe cases that do not undergo surgery.

RISK OF OVARIAN ENDOMETRIOMA IN SHIP Group 1 included 17 cases (89%) with stage III or IV endometriosis. Ovarian endometrioma was reported in seven cases, but extrapolation from literature reports suggests that it is likely that these were under-reported [69]. Pateman et al. [70] reported that the majority of endometriomas were observed to regress during pregnancy when followed up by serial ultrasound and that 12% of cases showed evidence suggestive of decidualization, such as a thick and irregular inner wall, papillary projections and high vascularity on Doppler examination. These features can pose diagnostic challenges because they may mimic ovarian malignancy. Pregnancy dependent changes in an ovarian endometrioma include rapid development of abundantly vascularized intracystic excrescences that regress at the end of pregnancy [71]. Although a recent literature review lends support to conservative management of endometrioma during pregnancy [72], COH+ET may constitute an additional risk factor for SHiP that should be taken into consideration.

A retrospective study of the outcome of ovarian endometriosis during pregnancy included two cases with pregnancy after IVF. Among 24 ovarian endometriomas

158 observed during pregnancy, the size of the cyst increased significantly during the second trimester in the two IVF cases. One of these subsequently ruptured and one developed an abscess [15]. Nevertheless, there remains a lack of consensus about the optimal management of endometrioma in women undergoing IVF [73].

Although 17b-E2 and P concentration in peritoneal fluid and serum are comparable during the normal menstrual cycle [74], local P concentrations are significantly higher in the peritoneum close to the corpus luteum compared with other peritoneal samples and systemic blood [75]. This suggests that endometriotic implants near the ovaries are more likely to undergo decidual changes in the first trimester of pregnancy as observed in typical peritoneal implants [76].

THE PATHOLOGY OF SHIP IN WOMEN WITH DECIDUOSIS OR ENDOMETRIOSIS Pathologic evaluation of bleeding sites reveals decidualized stromal cells, including in patients without visible endometriosis. Glandular cells were seen in few cases and were reported as atrophic. The histopathology of groups 1 and 2 was characterized by the presence of decidual cells. There are no case reports with histopathology from group 3; but the high prevalence of decidualization during pregnancy suggests that similar findings may be possible.

A second significant finding is the occurrence of bleeding from submesothelial ectopic decidua. This is a phenomenon noted during pregnancy where multiple, irregularly distributed submesothelial deposits of decidual cells can be noted in the serosa of abdominal and pelvic organs [77,78,79]. 8

In the case described by Doyle and Phillips [6] the autopsy found the presence of a small peritoneal lesion on the lateral side of the pelvis as cause of the fatal hemoperitoneum. At microscopy the lesion showed hemorrhagic decidual tissue without chorionic villi. The very vascular decidual reaction was apparently the source of the fatal bleeding.

In a series of 10 cases, Zaytsev and Taxy [67] observed two cases of submesothelial ectopic decidua that had small amounts of free blood in the peritoneal cavity. A third finding is that reported by O’Leary et al. [7] of a case with vascular intrusion by decidual cells, suggesting a mechanism of damage and bleeding in the thin-walled vessels of the decidual nodule.

It can be speculated that the high, nonphysiologic P levels observed early in pregnancies achieved after COH+ET [66] can accelerate or exacerbate the decidualization process. As shown in the endometriosis control group, the presence of any stage of endometriosis can be a risk factor, although the link with severe endometriosis may be indirect through the indication for COH+ET.

159 Chapter 8

IMPLICATIONS FOR CLINICAL PRACTICE AND RESEARCH Our study raises important issues for clinical practice and research. First, awareness of the condition may enable earlier diagnosis. Second, the recognition that COH+ET in women with severe endometriosis may represent a significant risk factor for SHiP can affect the choice of treatment. It is possible but uncertain that embryo freezing with replacement in unstimulated cycles will be advantageous. In some women endometriosis may not have been diagnosed before pregnancy, which lends support to the recognition of risk factors such as the presence of neonatal uterine bleeding [80].

Research is needed to enhance the role of imaging in the early diagnosis and monitoring of women at high risk of SHiP. It remains possible that subclinical hemoperitoneum may play a role in major obstetric presentations, such as preterm labor or unexplained abdominal pain [81]. Further research is urgently indicated to examine the role of decidualization and the vascular changes at the site of bleeding in biopsies or resection specimen, such as adnexectomy or hysterectomy specimens.

STRENGTHS AND LIMITATIONS The study highlights an important clinical problem and suggests a possible preventative measure, but it is important to emphasize that because of the rarity of SHiP it was necessary to design this study as a retrospective literature review. Thus, conclusions are dependent on available publications and their details and quality. A possible bias inherent in this approach may lie in a greater likelihood of cases of SHiP identified after IVF to be submitted for publication. However, SHiP rather than IVF was the main focus in most reported cases, whereas the role of IVF attracted little or no attention.

Although it is recognized that decidualization is a very common feature of the subserosal tissue during pregnancy, the exact incidence and natural history of this finding remain little understood. Decidualization is associated with atrophy of the glandular component, which can render confident diagnosis of endometriosis difficult.

In conclusion, SHiP is a rare but potentially fatal complication for both the pregnant woman and her unborn child. In vitro fertilization in women with severe endometriosis may be a significant risk factor for SHiP.

160 REFERENCES

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162 39. Fatnassi R, Mikhinini I, Torki E, et al. Hemoperitoneum caused by spontaneous uterine varicose vein rupture during third trimester of pregnancy - a case report. Gynecol Obstet (Sunnyvale). 2015;5:4. 40. Díaz-Murillo R, Tobías-Gonzalez P, Lopez-Magallon S, Magdaleno-Dans F, Bartha JL. Spontaneous hemoperitoneum due to rupture of uterine varicose veins during labor successfully treated by percutaneous embolization. Case Rep Obstet Gynecol. 2014;2014:580384. 41. Lim PS, Ng SP, Shafiee MN, Kampan N, Jamil MA. Spontaneous rupture of uterine varicose veins: a rare cause for obstetric shock. J Obstet Gynaecol Res. 2014;40:1791–1794. 42. Shi Q, Zhou HG, Liu XR, Li JP. Spontaneous hemoperitoneum with intrahepatic cholestasis during the third trimester of pregnancy. Int J Gynecol Obstet. 2014;127:297–298. 43. Munir S, Lo T, Seaton J. Spontaneous rupture of utero-ovarian vessels in pregnancy. BMJ Case Rep. 2012;2012:bcr0220125904. 44. Al Qahtani NH. Spontaneous intraperitoneal haemorrhage during pregnancy. BMJ Case Rep. 2012;2012:bcr2012007113. 45. Detriche O, Vaesen S, Carlier C, Dutranoy JC, Givron O, Bosschaert P. Rupture spontanee de varices uterines pendant le troisieme trimestre de grossesse: approche diagnostique par IRM [Spontaneous rupture of varicose veins in the third trimester of pregnancy: diagnosis achieved by MRI]. J Gynecol Obst Biol Reprod (Paris). 2012;41:370–373. 46. Nguessan KL, Mian DB, Aissi GA, Oussou C, Boni S. Spontaneous rupture of uterine varices in third trimester pregnancy: an unexpected cause of hemoperitoneum. A case report and literature reviews. Clin Exp Obstet Gynecol. 2013;40:175–177. 47. Nakaya Y, Itoh H, Muramatsu K, et al. A case of spontaneous rupture of a uterine superficial varicose vein in midgestation. J Obstet Gynaecol Res. 2011;37:1149–1153. 48. Bloom SL, Uppot R, Roberts DJ. Case 32-2010: a pregnant woman with abdominal pain and fluid in the peritoneal cavity. N Engl J Med. 2010;363:1657–1665. 49. Giulini S, Zanin R, Volpe A. Hemoperitoneum in pregnancy from a ruptured varix of broad ligament. Arch Gynecol Obstet. 2010;282:459–461. 50. Pezzuto A, Pomini P, SteinkassererM, Nardelli GB, Minelli L. Successful laparoscopic 8 management of spontaneous hemoperitoneum at 15 weeks of pregnancy: case report and review of literature. J Min Invasive Gynecol. 2009;16:792–794. 51. Moreira A, Reynolds A, Baptista P, Costa AR, Bernardes J. Case report: intra-partum utero- ovarian vessels rupture. Arch Gynecol Obstet. 2009;279:583–585. 52. Rosales RG, Saldana MAC, Leal IA, Lopez JAC. Rotura espontanea de los vasos uterinos durante el embarazo: communicacion de un caso y revision bibliografia. [Spontaneous rupture of uterine vessels during pregnancy: report of one case and literature review]. Ginecologia y Obstetricia de Mexico. 2008;76:221–223. 53. Koifman A, Weintraub AY, Segal D. Idiopathic spontaneous hemoperitoneum during pregnancy. Arch Gynecol Obstet. 2007;276:269–270. 54. Fiori O, Prugnolles H, Darai E, Uzan S, Berkane N. Spontaneous uterine artery rupture during pregnancy in a woman with sickle cell disease: a case report. J Reprod Med Obstet Gynecol. 2007;52:657–658. 55. Safioleas MC, Moulakakis KG. A rare cause of intra-abdominal haemorrhage: spontaneous rupture of the splenic vein. Acta Chir Belg. 2006;106: 237–239. 56. Eckerling B, Goldman JA, Yado S. Spontaneous rupture of the splenic vein in pregnancy with massive retro- and intraperitoneal hemorrhage. Am J Surg. 1962;103:836–839. 57. Hanna WA, Myles TJ. Spontaneous intraperitoneal haemorrhage during pregnancy: report of three cases. Br Med J. 1964;1:1024–1026.

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164 79. Bolat F, Canpolat T, Tarim E. Pregnancy-related peritoneal ectopic decidua (deciduosis): morphological and clinical evaluation. Turk Patoloji Derg. 2012;28:56–60. 80. Brosens I, Benagiano G. Is neonatal uterine bleeding involved in the pathogenesis of endometriosis as a source of stem cells? Fertil Steril. 2013;100:622–623. 81. Kim CJ, Romero R, Chaemsaithong P, Kim JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol. 2015;213:S53–69.

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CHAPTER 9

Decidual bleeding as a cause of spontaneous hemoperitoneum in pregnancy and risk of preterm birth

Lier, M.C.I. Brosens, I.A. Mijatovic, V. Habiba, M. Benagiano, G.

Gynecol Obstet Invest. 2017;82:313-321 Chapter 9

ABSTRACT

BACKGROUND Spontaneous Hemoperitoneum in Pregnancy (SHiP) is a rare, life- threatening event, particularly relevant to women with endometriosis or deciduosis.

METHODS To determine the type of lesions leading to SHiP, a literature search was conducted of all published SHiP cases. From a total of 1339 publications, information on pathological findings at the bleeding site with histological data were found in 24 case reports (16 pregnant, 8 post-partum).

RESULTS Among pregnant women (81% primigravida), 75% had a diagnosis of endometriosis and 25% of deciduosis. Among postpartum women (38% primiparous), 63% had a diagnosis of deciduosis and 25% of endometriosis. In all cases except one, decidual cells, with or without glandular structures, were present at the bleeding site. Decidual vessels were described in seven cases and all exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. These vessels were significantly different from arteries seen in the secretory endometrium, showing that structural modifications take place during the initial stage of the remodelling of placental bed spiral arteries.

CONCLUSIONS During pregnancy, a link seems to exist between ectopic decidualization, particularly that occurring in endometriotic foci, and occurrence of SHiP. In addition, subclinical decidual bleeding may be a potential risk factor for preterm labour.

168 INTRODUCTION

Recent reports focused attention on the rare, yet life-threatening occurrence of spontaneous hemoperitoneum in pregnancy (SHiP). This may be particularly relevant to women with endometriosis or deciduosis if they are undergoing in vitro fertilization (IVF) treatment. This dramatic complication has been associated with high perinatal morbidity and even mortality, but the trigger of the spontaneous bleeding has not been established [1,2]. Although the aetiology of SHiP remains unknown and may be multifactorial, several theories have been proposed to explain the rare complication [Table 1]. The early reports describing this complication suggested venous rupture due to a sudden increase in venous pressure associated with muscular activity, defecation, coughing, lifting or coitus [3]. Increased pelvic congestion and blood flow, the tortuous path of the uterine and ovarian veins, their lack of valves and their distension with elevated intraluminal pressure may provide vascular conditions for the dramatic event [4].

Table 1 - Hypotheses formulated in the literature on the cause of spontaneous hemoperitoneum in pregnancy ------· Sudden increases in venous pressures associated with muscular activity, defecation, coughing, lifting or coitus [3] · Tortuous path of the uterine and ovarian veins, their lack of valves and their distension with elevated intraluminal pressure, although the presence of some additional vascular defect was postulated [4] · Chronic inflammation due to endometriosis making the utero-ovarian vessels more friable, or the resultant adhesions creating further tension to these vessels as the uterus expands during pregnancy [5, 6] 9 · Hemodynamic factors, as well as increased hormonal effects caused by pregnancy can lead to structural vessel changes able to impair the arterial wall [7] · Necrosis and shedding of the decidualized endometriotic lesions during the third trimester of pregnancy or following delivery [8] · Erosion of the uterine artery or its branches by endometriosis [9] · Possible relation between the site of placental implantation and rupture of uterine vessels [10] · Potential 2-step process of uterine artery rupture starting with circumscribed hematoma of the broad ligament causing compression of adjacent anatomic structures (ureter, bowel), followed by rupture into the abdominal cavity [11] · Progesterone resistance in endometriosis could trigger involution of the ectopic decidua surrounding uterine vessels, leading to peritoneal bleeding of unpredictable severity [12]

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For a better understanding of the pathogenesis of SHiP and in the absence of systematic studies of vascular changes occurring at the site of bleeding, we reviewed all case reports in search of information on pathological events at the site of bleeding.

MATERIAL AND METHODS

SEARCH STRATEGY AND ANALYSIS A Scopus search, undertaken on July 13, 2015, using the term “spontaneous hemoperitoneum in pregnancy”, produced a total of 480 publications, starting with the publication by Hodgkinson and Christensen in 1950 [3]. The search was extended by probing further into the list of references for additional case reports.

We also undertook a PubMed search using the terms “hemoperitoneum and pregnancy” February 1, 2016. This yielded 859 articles. We excluded cases related to uterine ruptures, ectopic pregnancies, ruptured cysts and other recognized causes of intra-abdominal bleeding. After reading the abstracts and, if relevant, the full papers, original cases were identified that included a description of the histopathology taken from the bleeding site. This search was limited to articles published in English. Although the purpose of this review is to examine the occurrence of hemoperitoneum during pregnancy, reports of SHiP during the postpartum period (up to six weeks after delivery) have been included as well.

Finally, we searched for relevant articles on “deciduosis”, defined by the presence of foci of decidualized mesenchymal cells, but absence of glandular cells, in the sub- peritoneum of pelvic or abdominal structures during pregnancy [13].

RESULTS

The search identified 91 cases of SHiP published between 1950 and 2016. Of these, 24 case reports included a histological description from a biopsy obtained from the bleeding site. In one postpartum case, the site of bleeding was not identified. The series includes 16 cases during pregnancy and eight cases of SHiP on the day of delivery, or during the postpartum period.

VASCULAR PATHOLOGY AT THE SITE OF BLEEDING Histopathology findings of available biopsies are summarized in Table 2. All case reports, except the one obtained in the postpartum period, indicate the presence of decidual cells with or without glandular structures, at the site of bleeding. Seven case reports included a description of blood vessels present in the biopsy.

170 Histopathology changes decidual tissue, Endometriotic changes decidual tissue, Endometriotic changes decidual tissue, Endometriotic Endometriosis changes decidual tissue, Endometriotic Hemorrhagic foci endometriosis, of decidual changes, atrophic dilated glands changes decidual tissue, Endometriotic Deciduosis endometriosis Decidualized changes decidual tissue, Endometriotic endometriosis Decidualized Endometriosis changes decidual tissue, Endometriotic Endometriotic tissue, decidual changes, thin– walled vessels Endometriotic tissue, decidual changes, distended vessel with disintegrated wall Decidual and vascular changes

9 Site of biopsy Near left ovary, bowel peritoneum Bladder bowel Douglas, of pouch peritoneum, Bladder Left tube fallopian adnexa Right Left tube fallopian nodes lymph Bowel, omentum surface/peritoneum, Uterine Left ovary (partial), left fallopian tube, adhesions parametrium adnexa, Right Left broad ligament, left adnexa/parametrium sacro-uterineRight ligament adnexa Right Left ligament/parametrium broad surfaceUterine Peritoneal lesion right lateral pelvic wall/pouch Douglas of Histopathology biopsies of from the bleeding site in cases spontaneous of hemoperitoneum during pregnancy Author Pregnancy Lier II) (Case [14] et al., 2017 Lier IX) (Case et al., 2017 [14] Lier XI) (Case et [14] al., 2017 [15] Loh et al., 2015 Cozzolino [16] et al., 2015 Aggarwal [17] et al., 2014 De Vincenzo [12] et al., 2013 Kondoh [18] et al., 2012 [19] Reif et al., 2011 Brouckaert [20] et al., 2010 Bouet et al., 2009 [21] Grunewald and Jördens, 2009 [22] Katorza et al., 2007 II) (Case [23] Aziz et al., 2004 [24] Muzimoto et al., [6] 1996 Doyle and Philips, [25] 1957 Table 2 - Table

171 Chapter 9 decidual decidual

Histopathology Hemorrhagic foci endometriosis, of changes, distended and angiomatous tissue Endometriosis, decidualization Ectopic decidualization Endometriosis, decidual changes Decidualization, intrusion vascular Decidual tissue Decidual changes, distended ruptured vessels Decidual tissue, vascular changes Site of biopsy Left uterovesical ligament Right ovary (cyst) Left ovary Pelvic adhesions Adnexa (bilateral) Uterine surface, adnexa (bilateral), parametrium surfaceUterine Omentum Histopathology biopsies of from the bleeding site in cases spontaneous of hemoperitoneum during pregnancy (continued) Author Intrapartum postpartum and Lier IV) (Case et al., 2017 [14] Zhang [26] and Lou, 2015 Boztosun [27] et al., 2012 Gao [28] et al., 2010 O’Leary et al., 2005 [29] Richter et al., [30] 1983 Sabatelle [31] and Winger, 1973 Hulme-Moir and Ross, [32] 1969 Table 2 - Table

172 Three of the 16 biopsies obtained during pregnancy included information about blood vessels at the bleeding site(s). Aziz et al. [24] described a focus of endometriosis and decidualization in a woman who was 30 weeks into her first pregnancy and demonstrated the presence of very thin-walled blood vessels in the decidualized stroma. Mizumoto et al. [6] documented the presence of ruptured vessels on the serosal surface of the uterine fundus at 20 weeks in a woman during her first pregnancy. Histology demonstrated an intense decidual reaction. The blood vessels were distended and exhibited disintegration of the vessel wall. Doyle and Philip [25] reported the autopsy finding of a very large quantity of blood and blood clots distending the peritoneal cavity of a 37-year-old woman who had SHiP with her first pregnancy. They identified a 2.5 x 2cm oval-shaped peritoneal lesion with raised edges on the right side of the pouch of Douglas. Microscopically, this exhibited haemorrhagic decidual tissue without chorionic villi. The blood vessels were distended and had a highly disorganized wall. This area with very vascular decidual reaction was presumed to be the source of the fatal haemorrhage.

Four of the eight case reports with biopsies obtained postpartum included description of vasculature. Lier et al. [14] described a case of late postpartum SHiP in a patient with ovarian endometriosis. Histologically, there was a vascular lesion with multiple distended vessels and haemorrhagic deposits. O’Leary et al. [29] published one case of massive postpartum SHiP in which, following supracervical hysterectomy, it was possible to identify the origin of brisk bleeding as a tumour-like mass. Bleeding was controlled by clamping and ligation of the left uterine artery at its origin from the hypogastric artery. Bilateral salpingo-oophorectomy was performed because of a presumptive diagnosis of a malignant lesion with multiple tumour-like masses located on both ovaries and on the left pelvic side-wall. Histopathology confirmed bilateral ovarian endometriosis with extensive decidualization but no malignant degeneration. A section of the hypogastric artery was examined: this exhibited decidualized stroma protruding into the large distended arterial lumen. Sabatelle and Winger [31] reported a case of severe intrapartum SHiP arising from a focus of ectopic deciduosis. The serosal 9 surface over the posterior lower uterine segment was roughened and exhibited marked decidual reaction with large blood-filled sinuses communicating with the surface. Multiple sections through the uterine wall revealed no evidence of laceration or haemorrhage within the myometrium. Hulme-Moir and Ross [32] reported a case postpartum SHiP presenting with abdominal pain one week after delivery. The woman had haemorrhagic appendices epiploicae in the transverse colon. Omental biopsy showed multiple small, well-defined foci of decidual cells in the fat immediately below the serosa. The small vessels were dilated and there was interstitial haemorrhage and early necrosis of some of the decidual cells. There were no glandular structures suggestive of endometriosis.

CLINICAL FEATURES OF SHIP As mentioned, the search identified 16 women with SHiP during pregnancy and eight women with SHiP on the day of delivery, or during the postpartum period [Table 3], from whom histological reports were available. Age in the first group ranged between 25 and 38 years and in the second group between 25 and 41 years.

173 Chapter 9 death Live birthLive birthLive birthLive birthLive Outcome 2x stillbirth 1x stillbirth,1x 1x neonatal1x (g) NA NA 1620 1245 1390 Birth 2400 weight ligation Caesarean intervention compression Hysterotomy, adnexectomy, suture-ligation suture-ligation salpingectomy salpingectomy Type of surgicalType Section, resection, resection, Section, Caesarean Section,Caesarean Caesarean Section,Caesarean Section,Caesarean Section,Caesarean coagulation, suture- 21 28 29 30 22 33 nal age age nal (weeks) Gestatio- loss (mL) 1100 1750 1500 2200 3500 3000 Blood uterus ligament/ rectosigmoid, near left ovary left uterosacral left uterosacral Site of bleeding right uterine vein ligament, bladder Left tube fallopian Descending colon,Descending Left fallopian tube, adhesions, surface Posterior right broad posterior side uterus side posterior Right ovary and right right round ligament, Right broad ligament, - - E E E E E E IVF IVF IVF IVF ART Deciduosis Endometriosis/ 0 0 0 0 1 0 Para 31 31 31 37 35 33 Age Clinical data [15] Author 2015 [16] 2015 2014 [17] 2014 (Case II) [14] (Case (Case XI)(Case [14] (Case IX)(Case [14] Loh et al., 2015 Loh et al., 2015 Lier et al., 2017 Lier et al., 2017 Lier et al., 2017 Aggarwal et al., Cozzolino et al., Pregnancy Table 3 - Table

174 birth 2x Live Stillbirth Stillbirth Still birth Live birthLive Live birth Outcome (42 weeks) (g) NA NA NA 890 1318 Birth 4665 1190, weight ligation tubectomy cystectomy, fetus in situ, intervention Coagulation, Adnexectomy, Adnexectomy, suture-ligation bowel resection, bowel Type of surgicalType hysterectomy with Caeserean SectionCaeserean Caesarean SectionCaesarean hemostasic agents Caesarean Section,Caesarean Caesarean Section,Caesarean coagulation, suture- 17 24 24 27 27 29 nal age age nal (weeks) Gestatio- ) ); nd st 700 900 (1 (2 loss (mL) 1500 2500 2600 3500 (TBL: Large 2475) Blood

st episode) nd ligament episode); adhesions (2 parametrium peritoneal and and peritoneal Right ovary (1 broad ligamentbroad Site of bleeding

omental surface 9 Right ovary, right left uterine artery, left fallopian tube, Left ovary (partial), Right sacro-uterineRight bowel, lymph nodes lymph bowel, Left ligament/ broad Posterior side uterus, Posterior side uterus, - - - - E E E E D D IVF IVF ART Deciduosis Endometriosis/ 0 0 0 0 0 2 Para 25 31 33 33 33 33 Age Clinical data (continued) [19] Author 2012 [18] 2012 2010 [20] 2010 2009 [21] 2009 [22] 2009 Bouet et al., al., 2013 [12] al., 2013 Kondoh et al., De Vincenzo et Reif et al., 2011 Reif et al., 2011 Grunewald et al. Brouckaert et al., Table 3 - Table

175 Chapter 9 NA death request) Stillbirth Livebirth (parental Neonatal (autopsy) Outcome Pregnancy Fetal death termination (g) NA NA NA NA 1250 Birth weight Unknown ligation (autopsy) intervention adhesiolysis, Adnexectomy Adnexectomy, Suture ligation, Maternal death Suture-ligation, Type of surgicalType Caeserean SectionCaeserean Caesarean SectionCaesarean Caesarean Section,Caesarean cystectomy, suture- haemostatic agents haemostatic 26 20 28 33 PP Day 12 nal age age nal (weeks) Gestatio- Intrapartum loss (mL) 2500 2000 3000 3000 4000 Large Blood ovary vessels fundus, Douglas ligament Ovarian cyst, parametrium Right adnexa, wall/pouch of Site of bleeding Enlarged/dilated Enlarged/dilated Left uterovesical parametrium, left Right lateral pelvic veins/serosa uterine uterine veins/serosa Left ligament/ broad posterior uterine wall - - - - - E E E D D IVF E, D ART Deciduosis Endometriosis/ 1 0 0 0 1 0 Para 25 31 37 28 30 33 Age Clinical data (continued) [23] [24] Author 1996 [6] 2015 [26] 2015 Doyle and and Doyle Katorza et al., (Case IV)(Case [14] 2007 II) (Case Lier et al., 2017 Zhang and Lou, Aziz et al., 2004 Muzimoto et al., Phillips, [25] 1957 Intrapartum postpartum and Table 3 - Table

176

NA NA NA NA NA Stillbirth Outcome PP = postpartum;

(g) NA NA NA NA NA NA Birth weight applicable; NA = not

iliac artery Explorative Explorative laparotomy intervention interventions adnexectomy Hysterectomy Hysterectomy, Hysterectomy, oophorectomy artery, bilateral laparotomy: no Type of surgicalType bilateral salpingo- Ligation left uterine Ligation left internal mL = millilitres;

PP PP PP PP PP PP Day 0 Day 3 Day 0 Day 0 Day 9 Day 11 nal age age nal (weeks) fertilization; Gestatio- vitro

800 loss (mL) 1500 2000 2000 3000 Blood IVF = in

Unknown g = gram;

(diffuse) ligament/ Omentum parametrium (bloodvessels) (bloodvessels)

Site of bleeding 9 left uterine artery No active bleeding active No ovarian adhesions, ovarian Bilateral pelvic and Left pelvic sidewall Posterior left broad posterior uterine wall uterine posterior E = endometriosis;

- - - - - E D D D D ART Unknown D = deciduosis;

Deciduosis Endometriosis/ 0 1 1 3 0 1 Para techniques;

41 25 25 23 29 36 Age reproductive

Clinical data (continued) [28] Author 2012 [27] 2012 1983 [30] 2005 [29] Richter et al., O’Leary et al., Sabatelle and Boztosun et al., Ross, [32] 1969 Gao et al., 2010 Hulme-Moir and Winger, 1973 [31] Winger, 1973 Table 3 - Table ART = assisted TBL = total blood loss.

177 Chapter 9

Among women with SHiP during pregnancy, 13 (81%) were primigravida, whereas in the second group, three (38%) had delivered for the first time. In the pregnant group, all had the diagnosis of endometriosis (75%) or deciduosis (25%), while in the intrapartum or postpartum group, five (63%) had the diagnosis of deciduosis and two (25%) of endometriosis. No information was available on the eighth case.

SHiP occurred in the pregnancy group between weeks 17 and 33 with a median of week 26 and was associated with a stillbirth or neonatal death rate of 56%.

DISCUSSION

ENDOMETRIOSIS AND DECIDUOSIS ARE ASSOCIATED WITH DECIDUAL BLEEDING Histopathology of the 24 biopsies obtained from the bleeding site in women with SHiP documented in all cases the presence of decidualised stromal cells. Decidual vessels were described in seven cases and invariably these exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. Craven et al. [33] documented that decidual arteries were significantly different from arteries seen in the secretory endometrium, leading to the conclusion that structural modifications take place during the initial stage of physiological remodelling of the placental bed spiral arteries, before the vessel is affected by intravascular and interstitial trophoblast invasion. The early arterial changes are characterized by more endothelial basophilia, vacuolization, loss of elastica and dilatation. In addition, some vessels show disorganized or hypertrophied smooth muscle layers. Similar structural alterations occur in endometrial arterioles in the decidua parietalis of intrauterine pregnancies and in cases with ectopic pregnancy.

This clearly shows that in the placental bed, decidual spiral artery remodelling starts before the beginning of cellular interaction between the vessel and the intravascular or interstitial trophoblast. These physiological changes transform the decidual and myometrial segments of some 50 spiral arteries in the placental bed and allow an appropriate blood flow into the placenta during the progression of pregnancy [34].

SHiP in patients with endometriosis raises the possibility of multiple bleeding sites in the pelvis. All of these need to be identified in order to achieve haemostasis. This can be very challenging as the large uterus obstructs access to the posterior pelvic cavity during pregnancy. The posterior pouch of Douglas can also be obstructed by the presence of endometriosis-related adhesions and multiple endometriotic implants.

The phenomenon of “deciduosis”, defined as extra-uterine decidualization of stromal cells, has been well described in the peritoneum, cervix and ovary. Although its

178 formation under hormonal stimulation suggests a relationship with endometriosis, the clinico-pathological process is distinct and deciduosis does not always indicate underlying endometriosis [35]. Büttner et al. [36] investigated biopsies taken from the omentum (n=60) and various abdominal organs (n=48) at the time of caesarean section or ectopic pregnancy at different gestational ages. Focal or diffuse deciduosis was observed in all cases. Vacuolar degeneration and fragmentation, which are manifestations of regressive changes of the decidual cells, were noted in cases of advanced pregnancy. In more than 80% of cases, blood vessels of the area with ectopic decidua showed proliferation and enlargement when compared to areas of normal fat tissue. Immunohistochemistry demonstrated hormone-induced metaplasia of the sub- mesothelial mesenchyme. The exact onset and involution of extra-uterine decidua is not known, but available observations suggest that it starts during the second or third month of pregnancy and its involution seems complete between 4 and 6 weeks post- partum. As a rule, deciduosis does not give rise to clinical symptoms. Abdominal pain similar to appendicitis, intra-abdominal haemorrhages and haematuria has only very rarely been observed. Markou et al. [37] examined 307 consecutive women at the time of Caesarean section and obtained biopsies from all (n=31) subjects who were noted to have a macroscopic peritoneal lesion. All biopsies showed histological evidence of decidualization. Women with visible deciduosis were more likely to report abdominal pain during pregnancy, but the finding of deciduosis was not linked to preeclampsia, preterm labour or fetal growth restriction. In this study, deciduosis was not related to endometriosis. In this group, the occurrence of pain may be secondary to subclinical hemoperitoneum or to degenerative changes during the regression phase of these lesions.

MECHANISMS OF ECTOPIC DECIDUAL BLEEDING We have previously reported that IVF in women with endometriosis increases the 9 risk of SHiP [2]. Emerging evidence suggests that endometriosis is associated with progesterone resistance characterized by suboptimal expression of target genes [38]. Therefore, it is tempting to speculate that “functional” progesterone withdrawal triggers the involution of the decidual phenotype of the ectopic endometrium surrounding distended parametrial arterioles, leading to peritoneal bleeding of unpredictable severity [39].

In recent years, molecular mechanisms of decidual uterine spiral arteries remodelling in early pregnancy have been investigated. These involve a coordinated series of events, including the creation of a decidual immune cell environment, vascular cell disruption and loss. This is followed by extra villous trophoblast colonization and completion by mid-pregnancy. Smith et al. [40] performed a detailed analysis of the spatial and temporal loss of vascular extracellular matrix in the walls of remodelling decidual spiral artery in early pregnancy. They immuno-stained serial sections of these vessels for a panel of extracellular matrix markers and showed that the initial

179 Chapter 9 stages of spiral artery remodelling are characterized by the loss of laminin, elastin, fibrillin, collagen types III, IV and VI from the basement membrane, vascular media and/or adventitia, and surrounding decidual stromal cells. Loss of extracellular matrix correlated with disruption and disorganization of vascular smooth muscle cells. The majority of changes occurred prior to extensive colonization of the vessel wall by extravillous trophoblast. Given the co-distribution of uterine natural killer (uNK) cells and decidualized stromal cells, a mutual interaction might provide the correct regulatory environment in case of placentation [41]. The uNK cells and macrophages within remodelling vessels seem to prime decidual vessels for extravillous trophoblast invasion and to play a role in recruiting extravillous trophoblasts to line the vessel wall [42,43]. However, no information is available on the presence or potential role of uNK cells in ectopic decidualization. While plasma progesterone levels remain elevated throughout human pregnancy, as mentioned decidual bleeding in pregnancy may be elicited by a functional progesterone withdrawal, as indicated by significantly reduced decidual cell nuclear expression of progesterone receptor-A and –B. Functional withdrawal of progesterone results in increased phospho-ERK1/2 pathway initiating decidual bleeding and causing obstetrical complications such as abruption-induced preterm delivery [44]. Mechanical as well as cellular changes can contribute to the occurrence of SHiP. Changes in vessel wall can lead to weakening and increased predisposition to bleeding in response to trauma or increased pressure and can also render the vessels more friable resulting in difficulty in obtaining haemostasis. On the other hand, regression of deciduosis can itself lead to increased susceptibility and possibly vascular breakdown.

SUBCLINICAL DECIDUAL BLEEDING AS A POTENTIAL RISK FACTOR FOR PRETERM BIRTH A subset of patients with preterm labour has vascular lesions of the placental bed, including failure of physiological remodelling of the myometrial spiral arteries [34,45], a lesion that is common in preeclampsia. Understanding why some women with these vascular lesion and abnormal angiogenic profile develop preeclampsia and others preterm labour can provide insight into the pathophysiology of both conditions [46]. Pathogenetic mechanisms implicated in these disorders include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin-II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors [47]. Premature decidual senescence without progesterone withdrawal has been implicated in placentation disorders including preterm birth. The localization, severity and timing of the angiogenic imbalance, together with maternal susceptibility such as in the presence of endometriosis, may determine the clinical presentation. Recently, Marcellin et al. [48] demonstrated that decidua in women with endometriosis is able to generate endometriotic-like lesions in contact with the fetal membranes and found

180 significant deregulation for genes know to be enriched in processes involved among others in neoangiogenesis.

In a retrospective case study of preterm placentas Salafia et al. [49] suggested a relation between decidual hemosiderin deposition in the placenta or membranes and preterm delivery. A total of 196 of 462 (43%) preterm placentas or membranes had any decidual hemosiderin compared with one of 108 (0.8%) at term (p<0.00001). Sakata et al. [50] reviewed recent advances in hemo/iron-mediated signalling. Decidual haemorrhage may result in high levels of free heme and iron. Several important preterm birth-specific genes and proteins overlap with those known to be regulated by iron. Free iron oxidatively modifies lipid and protein, leading to DNA and cell damage. Collectively, decidual haemorrhage and inflammation are considered to be major contributors to the pathogenesis of preterm birth. Although the majority of patients with hemosiderin deposition had no history of gestational bleeding, this is an area where more research is needed.

The phenomenon of ectopic decidualization has traditionally been regarded as benign, but accumulating evidence suggests the need for systematic studies to further our understanding of the condition and its significance.

CONCLUSION

Available evidence suggests that during pregnancy a link exists between ectopic decidualization, particularly that occurring in endometriotic foci, and the occurrence of SHiP. Alterations in vessels’ walls have been demonstrated in the few cases where relevant biopsies were obtained and examined. Indeed, it seems that arterioles can 9 become modified in the absence of trophoblast. There is a need to carefully examine vascular alterations at the site of bleeding leading to SHiP to gain information on the pathophysiology of this serious complication. Finally, whereas there are indications that subclinical decidual bleeding may be a potential risk factor for preterm labour, further clinical, pathological and molecular investigations are required.

181 Chapter 9

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182 21. Bouet P-E, Sentilhes L, Lefebvre-Lacoeuille C, Catala L, Gillard P, Descamps, P. Endometriosis and spontaneous rupture of uterine vessels with hemothorax during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2009;144:95-96. 22. Grunewald C, Jördens A. Intra-abdominal hemorrhage due to previously unknown endometriosis in the third trimester of pregnancy with uneventful neonatal outcome: a case report. Eur J Obstet Gynecol Reprod Biol. 2010;148:204-205. 23. Katorza E, Soriano D, Stockheim D, et al. Severe intra-abdominal bleeding caused by endometriotic lesions during the third trimester of pregnancy. Am J Obstet Gynecol. 2007;197:501.e1–4. 24. Aziz U, Kulkarni A, Lazic D, Cullimore JE. Spontaneous rupture of the uterine vessels in pregnancy. Obstet Gynecol. 2004;103:1089-1091. 25. Doyle GB Phillips DL. Fatal intraperitoneal haemorrhage during pregnancy. BJOG. 1957;64:270- 271.

26. Zhang Z, Lou J. Hemoperitoneum after administration of prostaglandin E2 for induction of labour. Case Report Obstet Gynecol. 2015;2015:659274. 27. Boztosun A, Sümer D, Çetin M, Ali Çetin A. Idiopathic spontaneous hemoperitoneum during early postpartum period: Case Report. Turkiye Klinikleri J Med Sci. 2012;32:1718-1720. 28. Gao JL, Lortie K, Singh SS. Laparoscopic Internal Iliac Artery Ligation for Postpartum Spontaneous Hemoperitoneum. J Obstet Gynaecol Can. 2010;32:1172-1175. 29. O’Leary SM. Ectopic decidualization causing massive postpartum intraperitoneal hemorrhage. Obstet Gynecol. 2006;108:776-779. 30. Richter MA, Choudhry A, Barton JJ, Merrick RE. Bleeding ectopic deciduas as a cause of intraabdominal haemorrhage. A case report. J Reprod Med. 1983;28:430-432. 31. Sabatelle R, Winger E. Postpartum intraabdominal hemorrhage caused by ectopic deciduosis. Obstet Gynecol 1973;41:873-875. 32. Hulme-Moir I, Ross MS. A case of early postpartum abdominal pain due to haemorrhagic deciduosis peritonei. J Obstet Gynaecol Br Commonw. 1969;76:746-749. 33. Craven CM, Morgan T, Ward K. Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta. 1998;19:241-252. 34. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are 9 associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204:193-201. 35. Zaytsev P, Taxy JB. Pregnancy-associated ectopic decidua. Am J Surg Pathol. 1987;11:526-530. 36. Büttner A, Bässler R, Theele C. Pregnancy-associated ectopic decidua (deciduosis) of the greater omentum. An analysis of 60 biopsies with cases of fibrosing deciduosis and leiomyomatosis peritonealis disseminata. Pathol Res Pract. 1993;189:352-359. 37. Markou GA, Goubin-Versini I, Carbunaru OM, Karatzios C, Muray JM, Fysekidis M. Macroscopic deciduosis in pregnancy is finally a common entity. Eur J Obstet Gynecol Reprod Biol. 2016;197:54-58. 38. Bulun SE, Cheng YH, Yin P, et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248:94-103. 39. Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril. 2009;92:1243-1245. 40. Smith SD, Choudhury RH, Matos P, et al. Changes in vascular extracellular matrix composition during decidual spiral arteriole remodeling in early human pregnancy. Histol Histopathol. 2016;31:557-571. 41. Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12:1065-1074.

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42. Dunn CL, Kelly RW. Decidualization of the human endometrial stromal cell: an enigmatic transformation. Reprod BioMed Online. 2003;7:151-161. 43. Lash GE, Otun HA, Innes BA, et al. Interferon-gamma inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels. FASEB J. 2006;20:2512-2518. 44. Lockwood CJ, Kayisli UA, Stocco C, et al. Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells. Am J Pathol. 2012;181:2138-2148. 45. Kim YM, Bujold E, Chaiworapongsa T, et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2003;189:1063-1069. 46. Romero R, Dey SK, Fisher SJ. Preterm labor: One syndrome, many causes. Science. 2014;345:760-765. 47. Chaiworapongsa T, Romero R, Whitten AE, et al. The use of angiogenic biomarkers in maternal blood to identify which SGA fetuses will require a preterm delivery and mothers who will develop pre-eclampsia. J Matern Fetal Neonatal Med. 2016;29:1214-1228. 48. Marcellin L, Santulli P, Gogusev J, et al. Endometriosis also affects the decidua in contact with the fetal membranes during pregnancy. Hum Reprod. 2015:30:392-405. 49. Salafia CM, Pezzullo JC, López-Zeno JA, Simmens S, Minior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol. 1995;173:1097-1105. 50. Sakata M, Sado T, Kitanaka T, et al. Iron-dependent oxidative stress as a pathogenesis for preterm birth. Obstet Gynecol Surv. 2008;63:651-660.

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185

CHAPTER 10

Summary General discussion and future perspectives Chapter 10

SUMMARY

This thesis focused on the pathophysiological aspect of endometriosis. This was presented in two parts; part I focused on the enhancement of surgical diagnosis and (fertility) treatment in endometriosis patients, part II focused on the consequences of endometriosis in pregnancy.

ENHANCEMENT OF SURGICAL DIAGNOSIS AND TREATMENT Laparoscopic identification, including histological verification, remains the gold standard for diagnosing endometriosis [1]. However, due to the polymorphic appearance of endometriotic tissue, laparoscopic visualization could be impaired. Especially non-pigmented lesions may be hard to distinguish from healthy peritoneum [2-4]. In Chapter 2 we evaluated the available literature reporting on the use of enhanced laparoscopic imaging techniques in endometriosis surgery. Based on the results of nine studies (mainly cohort studies), including 432 patients, we concluded that enhanced laparoscopic imaging techniques have the potential to detect endometriosis with a better sensitivity and equal specificity when compared to conventional 2D white-light laparoscopy. In Chapter 3 we investigated the use of enhanced laparoscopic imaging techniques in a clinical trial and showed that with the combined use of 3D white-light imaging and narrow-band imaging (NBI), the sensitivity rates for the laparoscopic detection of endometriosis significantly improved (91.2% vs 75.8%, p<0.001) when compared to 2D white-light imaging. The single use of NBI or near- infrared imaging with indocyanine green (NIR-ICG) showed no additional value. By improving the laparoscopic detection of endometriosis, diagnosing endometriosis as well as surgical treatment of endometriosis can be improved with the potential of reducing recurrences. However randomized controlled trials are needed to establish whether an improved laparoscopic detection of endometriosis results in a more complete resection affecting long-term clinical outcomes in a favorable way.

ENHANCEMENT OF FERTILITY TREATMENT Endometriosis is in up to 50% of patients associated with subfertility [5]. IVF/ICSI- treatment is therefore frequently applied to women with endometriosis in order to overcome the endometriosis associated fertility problems. However, lower success rates of IVF/ICSI are reported, especially in patients with moderate to severe endometriosis (ASRM stage III-IV) and in patients with ovarian endometriomas [6-9]. Therefore is it recommended by the ESHRE guideline to pre-treat these women with a GnRH agonist prior to IVF/ICSI in order to increase the chances of pregnancy [1]. However this recommendation is debated since it is based on only three small studies, executed in a different IVF/ICSI-treatment era including different study-populations with varying degrees of endometriosis (ASRM stage II – IV). Recently, a revised version of the Cochrane systematic review reporting on the use of long-term GnRH agonist therapy prior to IVF/ICSI in endometriosis patients, was published [10]. In comparison

188 to the previous version of the Cochrane systematic review [11], the conclusion was downgraded towards uncertainty whether GnRH agonist treatment prior to IVF/ICSI may positively affect reproductive outcomes in patients with endometriosis [10]. In Chapter 4 we therefore described a protocol of a non-inferiority randomized controlled trial (COPIE trial: Continuous use of Oral contraceptives as an alternative for long term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients; Dutch Trial Register ref. no. NTR6357), which will investigate the use of continuously administered oral contraceptives as an alternative pre-treatment strategy compared to long-term pituitary desensitization with a GnRH-agonist in endometriosis patients undergoing IVF/ICSI treatment. Observational data show that treatment with oral contraceptives is favorable in patients with severe endometriosis undergoing IVF/ICSI treatment, as clinical pregnancy rates are reported higher in comparison to endometriosis patients treated without oral contraceptives and comparable to that of control patients without endometriosis [12]. However, a randomized comparison between continuous use of oral contraceptives and GnRH agonist treatment prior to IVF/ICSI in patients with endometriosis has not yet been made. The COPIE study is currently recruiting participants in six Dutch centers and will investigate treatment efficacy, as well as treatment safety, patient preferences and cost-effectiveness of both interventions. Alongside this randomized trial a prospective cohort study is running in which patients who do not wish to be randomized will be included. In 2015 the Dutch Society for Obstetrics and Gynaecology (Nederlandse Vereniging voor Obstetrie en Gynaecologie) prioritized the objective of this study as an important knowledge gap in reproductive medicine. Besides, the trial is supported by the Dutch patient association for women with endometriosis (Dutch Endometriosis Society) as well as Freya.

As mentioned previously, endometriosis related subfertility might as well be based on an impaired endometrial receptivity. In order to investigate whether uterine bathing with a pharmacologically neutral gel (ExEm gel) prior to IVF/ICSI treatment improves live birth rate after fresh embryo transfer, the TUBIE trial (Trial on Uterine Bathing before 10 IVF/ICSI treatment in patients with Endometriosis) was conducted and described in Chapter 5. A multicenter randomized, placebo-controlled clinical trial, which was performed in four endometriosis referral centers in the Netherlands and Belgium. A formal interim analysis was performed when 50% of the patients completed the trial and revealed no significant difference in primary outcome. The live birth rate after fresh embryo transfer was 16/60 (26.7%) after GIS versus 8/52 (15.4%) after sham procedures (relative risk (RR) 1.73, 95% confidence interval (CI) 081-3.72; p value 0.147). Besides, uterine bathing resulted in a higher pain score compared with a sham procedure (VAS score 2.7 [1.3-3.5] versus 1.0 [0.0-2.0], p<0.001). Therefore, we concluded that uterine bathing with ExEm gel is not advised as routine add-on to IVF/ICSI-treatment in women with endometriosis.

189 Chapter 10

ENDOMETRIOSIS IN PREGNANCY In part II of this thesis we discuss the pathophysiological aspects of endometriosis in pregnancy, especially the occurrence of Spontaneous Hemoperitoneum in Pregnancy (SHiP). SHiP is defined as a “spontaneous (nontraumatic) intraperitoneal hemorrhage during pregnancy and up to 42 days postpartum, requiring surgical intervention or embolization, excluding ectopic pregnancy, uterine rupture and caesarean section associated bleeding” [13]. To gain more insight in this assumed rare, but potentially life-threatening complication of pregnancy, we collected Dutch cases of SHiP in collaboration with the Dutch Working Group on Endometriosis. Eventually 15 cases of SHiP were identified and published in the largest original case series addressing this topic. In this case series, described in Chapter 6, we offer important practical take-home messages for the management of this phenomenon. To further improve the outcome of pregnancies complicated by SHiP, gaining and growing knowledge was advocated. Therefore a systematic review of the international literature was conducted (Chapter 7) evaluating the clinical course and pregnancy outcomes of SHiP. Endometriosis was present in 56% of the cases (33/59 cases), an association between the severity of SHiP and the stage of endometriosis could however not be established, consistent with the outcome of an earlier review [14]. SHiP seemed to occur predominantly in the third trimester of pregnancy (51%) and the main presenting symptom was (sub)acute abdominal pain (95%). For the first time recurrence of SHiP was reported in 8.5% of the cases. Since the exact etiology of SHiP is unknown and preventive measures are lacking, identifying risk factors is of importance in order to detect patients which may develop SHiP. In Chapter 8 we described that, besides endometriosis, the use of controlled ovarian stimulation for artificial reproductive techniques (ART) contributes to the occurrence and severity of SHiP. This seems of importance since subfertility and the concomitant use of ART are more common in women diagnosed with moderate to severe endometriosis [15]. In Chapter 9 the types of lesions that lead to SHiP were identified. After collecting information on the pathological and histological findings of SHiP lesions, we showed that a link exists between decidualization in ectopic endometrium and the occurrence of SHiP.

190 GENERAL DISCUSSION AND FUTURE PERSPECTIVES

ENHANCEMENT OF SURGICAL DIAGNOSIS AND TREATMENT Endometriosis is a challenging disease and affects approximately 2 to 10% of women of reproductive age, and up to 50% of women presenting with infertility or chronic pelvic pain [5,16]. Despite this high prevalence, diagnosing endometriosis remains challenging due to a high variation in presenting symptoms. A combination of these symptoms, findings at physical examination and imaging can increase the suspicion on endometriosis. However, laparoscopic identification, including histological verification, is nowadays still the gold standard for the definitive diagnosis of endometriosis [1]. Although laparoscopic treatment of visible endometriosis is associated with a decrease of overall pain complaints and increased live birth rate [1,17], high recurrence rates of the disease have been described post-surgery [18]. This is partly explained by the impaired visual potential of 2D white-light imaging in detecting endometriosis, since you can not treat what you do not see. Enhancement in the laparoscopic visualization of endometriosis may result in a more complete resection of the disease and therefore possibly improve clinical outcomes.

The use of enhanced laparoscopic imaging techniques, using optic techniques or fluorescent agents to visualize neovascularization in endometriotic lesions, are promising in the improvement of the intra-operative identification of endometriosis. In our systematic review three techniques were described [19]. 5-ALA fluorescence (5-ALA), autofluorescence imaging (AFI) and narrow-band imaging (NBI) showed a better detection rate for peritoneal endometriosis when compared to conventional 2D white-light (2D) laparoscopy. In the following diagnostic accuracy study 3D white-light (3D) imaging, near-infrared imaging with indocyanin green (NIR-ICG), AFI and NBI were evaluated [20]. Resulting in an improved sensitivity rate (83.5% vs. 75.8%, p = 0.016) and a non-inferior specificity rate (82.4% vs. 84.7%, p = 0.009) when 3D white-light imaging was compared to 2D white-light imaging. The single use of NBI or NIR-ICG showed 10 no improvement in the detection of peritoneal endometriosis. Combining the results of 3D white-light imaging and NBI in a post-hoc analysis resulted in a significantly improved detection rate of endometriotic lesions of 91.2% (p < 0.001) [20]. Nowadays improved endoscopy systems are available with the ability to directly combine 3D white-light imaging and NBI during laparoscopic surgery. Further exploration of the use of enhanced laparoscopic imaging techniques in a large randomized clinical trial is needed, taking into account long-term clinical outcomes like quality of life, recurrence free interval after surgery and need for reinterventions.

Although the diagnostic value of fluorescence guided imaging by NIR-ICG for peritoneal endometriosis is questionable [21] it might be of value for intra-operative (real time) intestinal and ureteral assessment and visualization of deep endometriosis. The use of NIR-ICG might facilitate the identification of the course of the ureter and helps to

191 Chapter 10 separate endometriotic nodules from healthy tissue, especially when the anatomy is distorted [22-25]. However, the optimal ICG dose and ICG exposure time before exploration is, beside the clinical applicability and safety, still not clearly established [26,27].

The roll of augmented reality in endometriosis surgery, in which preoperative medical images are projected on real time intraoperative images, is still being developed. It might provide improved intraoperative guidance by visualizing hidden risks and targeted anatomical structures during surgery, and may therefore facilitate the performance of complex surgical procedures as may be encountered in severe multi- organ endometriosis [28,29].

ENHANCEMENT OF FERTILITY TREATMENT Endometriosis and infertility are closely related. Although the exact mechanisms are not yet fully revealed, the disorder is a contributing cause of infertility in up to 50% of the couples who want to conceive [5,30,31]. The impaired ability to conceive may be explained by an altered folliculogenesis, hostile peritoneal environment, poor oocyte quality, impaired ovarian reserve, tubal dysfunction, decreased implantation capacity of the embryo, reduced endometrial receptivity and/or concomitant adenomyosis [32-36].

Uterine receptivity plays a crucial role in establishing a successful pregnancy, and may limit ART success in women with endometriosis [37], resulting in reduced pregnancy and live birth rates after IVF/ICSI. [6,38,39]. Coexistence of adenomyosis, found in approximately one third of the patients with endometriosis, can be additionally relevant as contributing factor to infertility [35,40]. Angiogenesis seems to play a crucial role in the pathophysiology of both diseases, in which endometrial cells acquire invasive properties to establish at ectopic foci in and outside the uterus [41-43]. Polymorphisms in angiogenic factors, like fibroblast growth factor 1 and 2, are associated with an increased risk of developing both diseases [42]. It is likely that an increased angiogenesis, resulting in formation of fragile blood vessels in the eutopic endometrium, might lead to an impaired endometrial receptivity in adenomyosis patients [44]. In women with endometriosis, clinical pregnancy and implantation rates after IVF/ICSI treatment are reduced when adenomyosis is concomitantly present. Besides, an increased risk of early pregnancy loss is observed after IVF/ ICSI treatment [35,45].

The impaired endometrial receptivity in women with endometriosis may also be explained by an inflammation mediated production of estradiol, increased endometrial resistance to progesterone and/or a defective decidualization of the stroma [34,46- 50]. In the epithelium, the progesterone resistance leads to an estrogen dominance which results in an increased proliferation. This is accompanied with an increase in aromatase expression and secretory phase estrogen receptor expression. In the endometrial stroma, the progesterone resistance will lead to defective decidualization

192 which is initiated by downregulation of ARID1A, an anti-inflammatory protein. All in all, these changes in the endometrial epithelium and stroma result in a non-receptive endometrium which resembles the endometrium of the late secretory phase of the menstrual cycle [51].

Whether a decreased expression of implantation markers during the window of implantation, plays a role in the decreased endometrial receptivity in endometriosis patients is still a matter of debate. Nowadays, it is possible to catalog the receptivity of the endometrium based on the transcriptomic profile. The Endometrial Receptivity Array (ERA) has emerged as a new diagnostic tool for determining the optimal window of implantation by examining the expression of a panel of 238 genes that are related to endometrial receptivity. By reporting the endometrium as pre-receptive, receptive or post-receptive, the optimal time frame for performing embryo-transfer during IVF/ICSI treatment can be determined [52,53]. Surprisingly, the expression of genes present in the ERA during the implantation window were not significantly different among patients with and without endometriosis, and did not depend on the severity of the disease [54]. This was recently confirmed in a Brazilian case control study, investigating the endometrial transcriptome by next generation sequencing, revealing no differentially expressed genes in endometriosis patients when compared to controls [55].

Identifying defects in endometrial receptivity in endometriosis patients, provide possible treatment strategies to overcome infertility. As such, a new test for endometrial receptivity has been developed, based on the finding of overexpression of B-cell CLL/ lymphoma 6 (BCL6) in women with endometriosis, called the ReceptivaDx Test [56]. Endometrial protein BCL6 is a biomarker for endometrial inflammation and stimulates endometrial cytokine expression. Besides, a high expression of BCL 6 inactivates progesterone-mediated factors and may therefore account for progesterone resistance in endometriosis [57-59]. BCL6 expression is significantly higher in the secretory phase of patients with endometriosis versus controls [56] and is strongly associated with poor IVF/ 10 ICSI outcomes [60]. In a recent case control study, medical (using GnRH agonist therapy) or surgical treatment of women with suspected endometriosis and overexpression of BCL6, significantly improved reproductive outcomes following IVF/ICSI and lowered miscarriage rates [61]. These data are promising with regard to providing opportunities to overcome infertility in endometriosis patients inside and outside of IVF/ICSI treatment. However, randomized studies are necessary to establish the true clinical value of medical and surgical interventions in patients with BCL6 overexpression.

Contrary to abovementioned findings, the recent Cochrane systematic review reporting on medical treatment of endometriosis patients by long-term GnRH agonist therapy prior to IVF/ICSI, shifted its conclusion from favorable to uncertain whether GnRH agonist pretreatment positively affects reproductive outcomes and IVF/ICSI associated complication rates [10]. The COPIE trial (Continuous use of

193 Chapter 10

Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) investigates in patients with moderate to severe endometriosis (ASRM stage III-IV) scheduled for IVF/ICSI treatment, whether pretreatment with oral contraceptives can be an alternative to long- term pituitary desensitization with a GnRH agonist with regard to treatment efficacy [62]. In November 2020 the first patient was enrolled, and the trial is currently recruiting patients in the Netherlands (Dutch Trial Register NL5991). Alongside this randomized trial a prospective cohort study is running in which patients who do not wish to be randomized will be included.

Besides medical treatment to enhance IVF/ICSI outcomes, it has been hypothesized that local endometrial injury might also have a beneficial effect on endometrial receptivity and implantation [63,64]. Multiple studies have been performed to investigate this effect, and although methodological issues may have biased trail results [65], no convincing evidence exists to apply endometrial injury as an IVF add-on [66]. Despite that this treatment is rated, amber, by the Human Fertilisation and Embryology Authority (HFEA) [67], it is still the most offered IVF add-on in the UK [68]. Recently one of the largest randomized controlled trial on endometrial scratching was published [69], investigating 1364 women undergoing IVF treatment with their own oocytes. In line with recent evidence, this trial did not find any favorable effect of endometrial scratching when compared to a sham procedure. In addition, subgroup analysis did not identify any subpopulation, including endometriosis (8% of the trial population; N= 108), that might benefit from endometrial scratching [69].

As an alternative to scratching, the receptivity of the endometrium might also be affected by infusing fluids into the uterine cavity (“uterine bathing”). Recently the IVF- LUBE trial investigated the effectiveness of pre-IVF uterine bathing with Lipiodol® in women with endometriosis or repeated implantation failure. Unfortunately the trial was not sufficiently powered to show any difference between uterine bathing with Lipiodol® and standard IVF/ICSI [70]. In the TUBIE trial (Chapter 5), we investigated whether intrauterine infusion of a pharmacologically neutral gel, as an equivalent to endometrial injury, increased pregnancy rates after IVF/ICSI treatment in patients with endometriosis (ASRM I-IV). This was compared to a sham procedure in which the gel was infused in the vaginal fornix posterior. In both arms of the trial, ExEm-gel® was used as it does not contain components which may influence endometrial receptivity. We found no significant difference between uterine bathing compared to a sham procedure on live birth rate after fresh embryo transfer (26.7% vs. 15.4%, RR 1.73, 95% CI 0.81-3.72; p 0.147). The study was stopped prematurely after a formal interim analysis was performed, due to slow recruitment of participants and trial fatigue. Therefore the study was underpowered and no definite conclusions could be drawn. Since uterine bathing procedures were also associated with slightly higher pain scores

194 and a small number of adverse events, we do not advise to apply this intervention as routine add-on to IVF/ICSI treatment in patients with endometriosis.

Summarized, in order to achieve more effective therapies, novel treatment strategies must be developed looking specifically into the pathogenic mechanisms that are involved in endometriosis. As such, more knowledge on the use of immunomodulatory agents targeting inflammatory pathways and stem cell-based therapies is advocated in order to improve endometriosis treatment [71]. Furthermore, high quality research is necessary to accurately evaluate the diagnostic potential and clinical applicability of promising biomarkers, like BCL6, for identifying and correcting impaired endometrial receptivity in endometriosis patients.

BEYOND SUFBFERTILITY; PREGNANCY OUTCOMES IN ENDOMETRIOSIS PATIENTS Although endometriosis is closely related to infertility, the majority of patients (>80%) ultimately achieves pregnancy before the age of 40 [72]. It is not uncommon for patients with endometriosis to be advised that becoming pregnant might be beneficial in order to reduce their symptoms and alter the course of their disease. However, there is a growing amount of evidence pointing out that endometriosis may interfere with successful pregnancy outcomes [73,74].

As such, the role of endometriosis in the development of pregnancy (complications) and the impact of pregnancy on endometriosis, are growing areas of interest. Endometriosis related complications are mostly unreported and therefore underestimated in literature. They however may represent life-threatening events for both mother and baby, often requiring surgical intervention [73]. This points out the need for large observational studies to assess the true prevalence of these complications.

An acute complication of pre-existing endometriosis in pregnancy is SHiP (Spontaneous 10 Hemoperitoneum in Pregnancy). In collaboration with the Dutch working group on endometriosis we collected unreported Dutch cases of SHiP, resulting in the largest retrospective original case-series concerning this topic [75]. From this series we learned that SHiP usually presents with non‐specific symptoms, and as such any pregnant women with acute abdominal pain complaints, hypotension and/or signs of fetal distress in the second or third trimester of pregnancy, should immediately be examined physically and by adequate abdominal imaging. Imaging is an important diagnostic tool, as it can rule out obstetrical problems like uterine rupture or placental abruption, and can enhance the suspicion of SHiP by visualizing the presence of free intra-abdominal fluid. Often surgical intervention is mandatory, giving the opportunity for an accurate inspection of possible bleeding points on the posterior surface of the uterus and the utero-ovarian vessels located in the parametrium [76]. Histopathology findings of available biopsies of SHiP lesions show the presence of decidualized stromal cells,

195 Chapter 10 suggestive for a relation between ectopic decidualization, particularly that occurring in endometriotic foci, and the occurrence of SHiP [77]. Although a timely diagnosis and treatment of SHiP is associated with a good prognosis for the mother, perinatal mortality remains high over the last decades (>25%) [76]. Moreover, recurrence of SHiP within the same or a subsequent pregnancy has been described [75,76].

Although endometriosis and the use of controlled ovarian hyperstimulation in ART seems to be risk factors for the development of SHiP [14,76,78], it is nowadays still not possible to detect patients at risk of the development of SHiP. Besides, preventive measures are lacking. No evidence exists whether medical or surgical treatment of endometriosis before pregnancy, or applying a freeze-all strategy in ART, lowers the risk of SHiP. With the aim to further understand this rare complication of pregnancy and get insight in the exact incidence and prevalence of SHiP, several countries took the initiative to register the occurrence of SHiP in a prospective way, gathered in a multinational collaboration (INOSS). [79] Dutch cases have been registered from April 2016 – April 2018 by the Netherlands Obstetric Surveillance System (NETHOSS). A total of 18 cases have been reported and are currently further analyzed. Besides, to further unravel the pathophysiological mechanisms involved in SHiP, immunohistochemically evaluation of tissue samples taken from SHiP bleedings sites during surgery are required.

Next to the somatic aspect of SHiP, we recently investigated the psychological impact of SHiP. Previous studies showed that severe pregnancy complications can have a negative effect on QoL and future perspectives of patients [80]. We therefore interviewed patients with SHiP, and their partners, and asked them to complete two questionnaires investigating the impact of the event. SHiP had a profound impact on both (scored as an 8 or higher on a 0-10 scale). Patients described a freeze response at the moment of SHiP, combined with either an anxious reaction or a survival mode mind-set. All patients received psychological help after the SHiP event. The feeling of not being heard by the medical staff was reported by all women. The questionnaires showed lower QoL compared to reference groups.

Overall it can be concluded, since endometriosis related complications in pregnancy are rare, that pregnant women with endometriosis can be reassured on the course of their pregnancy and no extra monitoring is required. However, physicians should be aware of the potential increased risk of endometriosis associated pregnancy complications and should include SHiP in their differential diagnosis because of the potential life threatening course. Besides SHiP can have large impact on patients and partners and attention to psychological support is required.

196 RECOMMENDATIONS FOR CLINICAL PRACTICE

Based on the results of this thesis, focusing on the pathophysiological aspect of endometriosis, we have the following recommendations:

Part I Enhancement of surgical diagnosis and fertility treatment 1) The use of enhanced laparoscopic imaging techniques could be considered, especially 3D white light imaging combined with NBI, since it resulted in an improved detection of peritoneal endometriosis when compared to 2D white light imaging (Chapter 2 & 3). 2) More insight in the need of pre-treatment strategies for IVF/ICSI treatment in patients with endometriosis should be obtained (Chapter 4); 3) Uterine bathing procedures are not advised as routine add-on to IVF/ICSI-treatment in women with endometriosis (Chapter 5)

Part II Endometriosis in pregnancy 4) Increasing awareness of SHiP as a pregnancy complication is advocated, especially in women diagnosed with endometriosis and/or pregnant after the use of COH in ART (Chapter 6, 7 & 8); 5) In pregnant women presenting with (sub)acute abdominal pain, signs of hypovolemic shock and/or fetal distress in the second or first trimester of pregnancy, SHiP must be considered. In these patients imaging has been shown to be an important diagnostic tool which visualizes intra-peritoneal fluid and may rule out other complications in pregnancy (Chapter 6 & 7); 6) A link seems to exist between decidualization in ectopic endometrium and the occurrence of SHiP, but further immunohistochemically evaluation is needed in order to understand the pathophysiological mechanisms behind SHiP (Chapter 9). 10 FUTURE RESEARCH

In this thesis we focused on the pathophysiological aspects of endometriosis, with regard to enhancement of surgical diagnosis and (fertility) treatment and the effects of endometriosis on pregnancy outcomes.

We compared the use of enhanced laparoscopic imaging techniques in endometriosis therapy. Although we concluded that with the use of 3D white-light imaging and NBI peritoneal endometriosis could be detected with a better sensitivity and a non-inferior specificity rate when compared to 2D white-light imaging, more research is needed to establish whether an improved detection of endometriosis affects long-term clinical outcomes. Besides, additional research is needed to investigate the use of enhanced

197 Chapter 10 laparoscopic imaging techniques in surgery for deep endometriosis and its additional value regarding efficacy and safety.

More insight in the mechanisms that are responsible for the lower pregnancy rates in endometriosis patients is needed in order to develop novel treatment strategies. Since ART treatment is often applied to overcome endometriosis-related subfertility, it is of importance to investigate whether medical of surgical pretreatment of endometriosis can improve reproductive outcomes. Medical pretreatment of endometriosis patients (ASRM III-IV) undergoing ART is currently investigated by the COPIE trial, comparing the use of long-term pituitary desensitization with a GnRH agonist to the long-term use of oral contraceptives (Dutch Trial Register NL5991). Recruitment is expected to be completed in 2023 [62].

The effect of surgical pretreatment of deep (colorectal) endometriosis on reproductive outcomes is nowadays still a matter of debate. Only observational studies are available, showing different conclusions, with high heterogeneity and risk of bias. Only one retrospective matched cohort study showed higher live birth rates and pregnancy rates when ART was preceded by colorectal surgery [81]. Therefore the routine performance of a risky procedure to enhance fertility in women without occlusive symptoms of colorectal endometriosis should be questioned [82]. In this context a randomized controlled trial in France is currently recruiting patients (Endofert study; ClinicalTrals. gov NCT02948972). This study investigates in patients with colorectal endometriosis whether complete radical surgery prior to ART improves reproductive outcomes when compared to ART only. De recruitment is expected to be completed in 2021. Results of these above-mentioned ongoing trials are expected to guide future management of women with severe endometriosis undergoing ART, and can be helpful for shared- decisions making. Hopefully non-effective treatment strategies will be abandoned, increasing reproductive outcomes and reducing healthcare expenditures.

Endometrial receptivity seems to be pivotal in establishing a successful pregnancy and may limit ART success in women with endometriosis [37]. Although we found no significant effect of uterine bathing with sonography gel on live birth rate after fresh embryo transfer in endometriosis patients, it might be of importance to identifying endometriosis patients with impaired endometrial receptivity. Endometrial markers like BCL-6 may be helpful for this purpose. Identifying defects in endometrial receptivity may provide possible future treatment strategies. As such, more information is needed about the mechanisms of progesterone resistance in the endometrium of endometriosis patients: how is it developed and is it possible to reverse the resistance by medical or surgical therapy? In vitro cellular models may help to identify these changes in progesterone response and factors that influence the expression. Furthermore, application of experimental treatments with immunomodulatory and anti-inflammatory agents must be further evaluated [71].

198 Research on the relationship between endometriosis and adverse pregnancy outcomes has yielded mixed results. A recent systematic review concluded that there were a great deal of inconclusive as well as inconsistent findings, possibly influenced by significant heterogeneity across the available studies [73]. This is largely related to the population under study and the definition of endometriosis with variation in the need for pathologic confirmation. In addition, registry-based cohort studies may be prone to a misclassification of endometriosis and pregnancy outcomes, as a result of an over representation of severe disease phenotypes and limited information on confounders and modifying factors. Therefore, larger population based cohort studies are needed to clarify the relationship between endometriosis and adverse pregnancy outcomes. In order to develop screening or preventive interventions for pregnant women with endometriosis, future research should focus on the potential biological pathways underlying the relationship between endometriosis and adverse pregnancy outcomes.

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202 63. Nastri CO, Lensen SF, Gibreel A, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2015:CD009517. 64. Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25:561-571. 65. Li W, Suke S, Wertaschnigg D, et al. Randomised controlled trials evaluating endometrial scratching: assessment of methodological issues. Hum Reprod. 2019;34:2372-2380. 66. van Hoogenhuijze NE, Kasius JC, Broekmans FJM, Bosteels J, Torrance HL. Endometrial scratching prior to IVF; does it help and for whom? A systematic review and meta-analysis. Hum Reprod Open. 2019;2019:hoy025. 67. Lensen S, Shreeve N, Barnhart KT, Gibreel A, Ng EHY, Moffett A. In vitro fertilization add-ons for the endometrium: it doesn’t add-up. Fertil Steril. 2019;112:987-993. 68. Spencer EA, Mahtani KR, Goldacre B, Heneghan C. Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ Open. 2016;6:e013940. 69. Lensen S, Osavlyuk D, Armstrong S, et al. A Randomized Trial of Endometrial Scratching before In Vitro Fertilization. N Engl J Med. 2019;380:325-334. 70. Reilly SJ, Glanville EJ, Dhorepatil B, Prentice LR, Mol BW, Johnson NP. The IVF-LUBE trial - a randomized trial to assess Lipiodol® uterine bathing effect in women with endometriosis or repeat implantation failure undergoing IVF. Reprod Biomed Online. 2019;38:380‐386. 71. Lin YH, Chen YH, Chang HY, Au HK, Tzeng CR, Huang YH. Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies. Int J Mol Sci. 2018;19:2385. 72. Prescott J, Farland LV, Tobias DK, et al. A prospective cohort study of endometriosis and subsequent risk of infertility. Hum Reprod. 2016;31:1475–1482. 73. Leone Roberti Maggiore U, Ferrero S, Mangili G, et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. Hum Reprod Update. 2016;22:70-103 74. Leeners B, Damaso F, Ochsenbein-Kölble N, Farquhar C. The effect of pregnancy on endometriosis-facts or fiction? Hum Reprod Update. 2018;24:290‐299. 75. Lier M, Malik RF, van Waesberghe J, et al. Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series. BJOG. 2017;124:306-312. 76. Lier MCI, Malik RF, Ket JCF, Lambalk CB, Brosens IA, Mijatovic V. Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - A systematic review of the recent literature. Eur J Obstet Gynecol Reprod Biol. 2017;219:57‐65. 10 77. Lier MCI, Brosens IA, Mijatovic V, Habiba M, Benagiano G. Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth. Gynecol Obstet Invest. 2017;82:313‐321. 78. Brosens IA, Lier MC, Mijatovic V, Habiba M, Benagiano G. Severe spontaneous hemoperitoneum in pregnancy may be linked to in vitro fertilization in patients with endometriosis: a systematic review. Fertil Steril. 2016;106:692-703. 79. INOSS (Internet). Oxford: International Network of Obstetric Survey Systems (updated February 1st 2017). [https://www.npeu.ox.ac.uk/inoss]. Accessed May 20th 2020. 80. de Visser SM, Kirchner CA, van der Velden BGJ, et al. Major obstetric hemorrhage: Patients’ perspective on the quality of care. Eur J Obstet Gynecol Reprod Biol. 2018;224:146-152. 81. Bendifallah S, Roman H, Mathieu d’Argent E, et al. Colorectal endometriosis-associated infertility: should surgery precede ART? Fertil Steril. 2017;108:525‐531.e4. 82. Vercellini P, Viganò P, Frattaruolo MP, Borghi A, Somigliana E. Bowel surgery as a fertility- enhancing procedure in patients with colorectal endometriosis: methodological, pathogenic and ethical issues. Hum Reprod. 2018;33:1205‐1211.

203

Appendices

Nederlandse samenvatting PhD portfolio List op publications List of co-authors Dankwoord Over de auteur Appendices

NEDERLANDSE SAMENVATTING

Dit proefschrift is het resultaat van het promotieonderzoek van Marit C.I. Lier, met de naar Nederlandse vertaalde titel: ‘Endometriose; van diagnose naar implantatie en zwangerschap’.

Dit proefschrift focust zich op de pathofysiologische aspecten van endometriose. Het proefschrift is opgesplitst in twee delen: deel 1 focust zich op de verbetering van de chirurgische diagnose en (fertiliteits) behandeling van patiënten met endometriose, deel 2 focust zich op de consequenties van endometriose tijdens de zwangerschap.

VERBETERING VAN CHIRURGISCHE DIAGNOSE EN BEHANDELING Laparoscopische identificatie, inclusief histologische verificatie, is de gouden standaard voor de diagnose endometriose [1]. Echter, ten gevolge van het polymorfe uiterlijk van endometriose weefsel, kan de laparoscopische visualisatie worden beperkt. Met name niet-gepigmenteerde endometriose laesies zijn soms moeilijk te onderscheiden van gezond peritoneum [2-4]. In hoofdstuk 2 evalueren we de beschikbare literatuur welke rapporteert over het gebruik van laparoscopische visualisatietechnieken bij endometriose chirurgie. Gebaseerd op het resultaat van negen onderzoeken (voornamelijk cohort studies), waarbij in totaal 432 patiënten werden onderzocht, kon worden geconcludeerd dat met het gebruik van laparoscopische visualisatietechnieken endometriose kon worden gedetecteerd met een hogere sensitiviteit en gelijkblijvende specificiteit ten opzicht van conventionele 2D wit-licht laparoscopie. In hoofdstuk 3 hebben we het gebruik van laparoscopische visualisatietechnieken verder onderzocht in een klinisch onderzoek en aangetoond dat met het combineren van 3D wit-licht laparoscopie en ‘narrow-band imaging’ (NBI), de sensitiviteit voor laparoscopische detectie van endometriose significant verbeterde (91.2% versus 75.8%, P<0.001) in vergelijking met 2D wit-licht laparoscopie. Het enkele gebruik van NBI of “near- infrared imaging met indocyanine groen” (NIR-ICG) bleek niet van toegevoegde waarde. Door het verbeteren van de laparoscopische detectie van endometriose, kan zowel het diagnosticeren alsmede de chirurgische behandeling van endometriose worden verbeterd, met als gevolg een completere verwijdering van endometriose weefsel en een potentiële reductie van terugkeer van de ziekte. Gerandomiseerde onderzoeken zijn echter nodig om aan te tonen dat een verbeterde laparoscopische detectie van endometriose, resulteert in een meer complete resectie van endometriose en eveneens positieve invloed heeft op de lange termijn effecten na chirurgie.

VERBETERING VAN FERTILITEITSBEHANDELINGEN Endometriose komt voor bij ongeveer 50% van de patiënten met subfertiliteit [5]. IVF/ICSI-behandelingen worden daarom frequent toegepast bij patiënten met endometriose. Echter, lagere succeskansen worden beschreven, voornamelijk bij patiënten met matige tot ernstige endometriose (ASRM graad III-IV) en bij patiënten

206 met ovariële endometriose [6-9]. De ESHRE richtlijn adviseert daarom om deze groep patiënten voorafgaand aan de IVF/ICSI-behandeling te behandelen met een GnRH agonist om de kansen op zwangerschap te vergroten [1]. Deze aanbeveling staat echter ter discussie, omdat het achterliggende bewijs is gebaseerd op slechts drie kleine studies, uitgevoerd in een ander IVF/ICSI tijdperk, waarbij verschillende patiëntenpopulaties werden geïncludeerd met wisselende graderingen endometriose (ASRM graad II-IV).

Recent is een gereviseerde versie van de Cochrane systematische review gepubliceerd welke rapporteert over het langdurig gebruik van GnRH agonisten voorafgaand aan een IVF/ICSI-behandeling bij patiënten met endometriose [10]. In vergelijking met de vorige Cochrane systematische review [11], is de conclusie ten aanzien van het positieve effect op de reproductieve uitkomsten van GnRH agonist voorbehandeling bij patiënten met endometriose afgezwakt en gewijzigd naar ‘onzeker’ [10]. In hoofdstuk 4 beschrijven wij een onderzoeksprotocol van een gerandomiseerde studie (COPIE studie: Continuous use of Oral contraceptives as an alternative for long term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients; Nederlands Trial Register registratienummer: NTR6357), waarin onderzoek gedaan zal worden naar voorbehandeling middels de orale anticonceptiepil in een continu schema als een alternatief voor langdurige hypofysaire onderdrukking met een GnRH agonist voorafgaand aan een IVF/ICSI behandeling bij vrouwen met matig tot ernstige endometriose (ASRM graad III-IV). Observationele data laten zien dat behandeling met de orale anticonceptiepil gunstig is bij patiënten met ernstige endometriose voorafgaand aan de IVF/ICSI-behandeling, aangezien kansen op een klinische zwangerschap hoger zijn in vergelijking met patiënten zonder voorbehandeling en vergelijkbaar met controle patiënten zonder endometriose [12]. Een gerandomiseerde vergelijking tussen de behandeling met de orale anticonceptiepil versus behandeling met een GnRH agonist voorafgaand aan een IVF/ICSI-behandeling bij vrouwen met endometriose is echter nog niet gemaakt. De COPIE studie is momenteel actief patiënten aan het includeren in zes verschillende Nederlandse ziekenhuizen en onderzoekt de effectiviteit, veiligheid, patiënttevredenheid en kosteneffectiviteit van de twee verschillende voorbehandelingen. Naast dit gerandomiseerde onderzoek loopt een prospectief cohort onderzoek waarin patiënten worden geïncludeerd die niet gerandomiseerd willen worden. In 2015 heeft de Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG) de onderzoeksvraag van deze studie geprioriteerd als belangrijk kennishiaat binnen de voortplantingsgeneeskunde. Daarnaast wordt de studie ondersteund door patiëntenverenigingen de Endometriose Stichting en Freya.

Zoals reeds eerder genoemd, kan endometriose gerelateerde subfertiliteit eveneens gebaseerd zijn op een verminderde receptiviteit van het endometrium. Om te onderzoeken of ‘uterien baden’ met farmacologisch neutrale echo gel (ExEm gel) voorafgaand aan een IVF/ICSI-behandeling de kans op een levendgeborene na verse

207 Appendices embryo terugplaatsing zou verbeteren, werd de TUBIE studie (Trial on Uterine Bathing before IVF/ICSI treatment in patients with Endometriosis) uitgevoerd en beschreven in hoofdstuk 5. Een multicenter gerandomiseerd, placebo-gecontroleerd, klinisch onderzoek dat werd uitgevoerd in vier endometriose verwijs centra in Nederland en België. Een interim-analyse die werd uitgevoerd nadat 50% van de geplande studiepopulatie had deelgenomen aan de studie liet geen verschil zien in de primaire uitkomstmaat. Het aantal levendgeborene na verse embryo terugplaatsing was 16/60 (26.7%) na gel echo en 8/52 (15.4%) na placebo procedure (RR 1.73, 95% CI 0.81- 3.72; p 0.147). Het verrichten van een gel echo resulteerde in een hogere pijnscore in vergelijking tot een placebo procedure (VAS score 2.7 [1.3-3.5] versus 1.0 [0.0- 2.0], p<0.001). Het standaard toepassen van ‘uterien baden’ met echografische gel voorafgaand aan een IVF/ICSI-behandeling bij patiënten met endometriose wordt daarom niet geadviseerd.

ENDOMETRIOSE IN DE ZWANGERSCHAP In deel 2 van dit proefschrift worden de pathofysiologische aspecten van endometriose in de zwangerschap bediscussieerd, met name het voorkomen van een spontaan hemoperitoneum in de zwangerschap (SHiP; Spontaneous Hemoperitoneum in Pregnancy). SHiP wordt gedefinieerd als een ‘spontane (niet traumatische) intra peritoneale bloeding die optreedt in de zwangerschap of tot 42 dagen postpartum, waarbij chirurgische interventie of embolisatie noodzakelijk is. Exclusief buitenbaarmoederlijke zwangerschappen, uterus rupturen en bloedingen ten gevolge van een keizersnede’ [13]. Om meer inzicht te krijgen in deze zeldzame, maar potentieel levensgevaarlijke, complicatie van de zwangerschap werd, in samenwerking met de Nederlandse Werkgroep Endometriose, Nederlandse SHiP casuïstiek verzameld. Uiteindelijk konden 15 originele SHiP cases worden geïdentificeerd en gepubliceerd in de grootste originele case-serie aangaande dit onderwerp. In deze case-serie, beschreven in hoofdstuk 6, worden belangrijke praktische take-home boodschappen gegeven voor behandeling van dit ziektebeeld. Om de uitkomsten van zwangerschappen die gecompliceerd worden door SHiP verder te verbeteren is meer kennis noodzakelijk. Daarom werd een systematisch review geschreven met de beschikbare internationale literatuur (hoofdstuk 7) waarin het klinische beloop van en de zwangerschapsuitkomsten na SHiP worden geëvalueerd. Endometriose was aanwezig in 56% van de gevallen (33/59 cases), een associatie tussen de ernst van SHiP en het stadium van endometriose kon echter niet worden vastgesteld, overeenkomstig met eerdere literatuur [14]. SHiP ontstond voornamelijk in het derde trimester van de zwangerschap (51%) waarbij het voornaamste symptoom waarmee patiënten zich presenteerden een (sub)acuut ontstane abdominale pijn was (95%). Voor het eerst in de literatuur werd het herhaaldelijk voorkomen van SHiP gerapporteerd in 8.5% van de cases. Omdat de exacte etiologie van SHiP nog onbekend is en preventieve maatregelen ontbreken, is het identificeren van risico factoren van groot belang om hoog risico patiënten te detecteren. In hoofdstuk 8 wordt beschreven dat, naast endometriose,

208 het gebruik maken van ovariële hyperstimulatie bij fertiliteitsbehandelingen bijdraagt aan het vóórkomen en de ernst van SHiP. Dit lijkt van belang gezien subfertiliteit en het gelijktijdig gebruik maken van fertiliteitsbehandelingen vaker voorkomen bij vrouwen met matige tot ernstige endometriose [15]. In hoofdstuk 9 werden de type laesies die resulteren in SHiP geïdentificeerd. Na het verzamelen van informatie over de pathologisch en histologische bevindingen van SHiP laesies, werd aangetoond dat er een connectie bestaat tussen decidualisatie in ectopisch endometrium en het vóórkomen van SHiP.

209 Appendices

PHD PORTFOLIO

Name Marit C.I. Lier PhD period March 2014 – January 2021 Promotores prof.dr. V. Mijatovic prof.dr. C.B. Lambalk Courses BROK (Basiscursus Regelgeving Klinische Onderzoeken) 2014 Practical Biostatistics 2016

Oral presentations - Recidief zwelling in sectio-litteken; een onverwachts beloop. Refereeravond 2017 cluster Obstetrie & Gynaecologie Academisch Medisch Centrum (AMC) en VU medisch centrum (VUmc), Amsterdam, the Netherlands. 1st prize Best Presentation - Laparoscopic imaging techniques in endometriosis therapy: a pilot trial and 2017 systematic review of the literature. 13th World Congress on Endometriosis (WCE), Vancouver, Canada. 2nd prize Best Clinical Presentation - Spontaneous Hemoperitoneum in Pregnancy (SHiP) en Endometriose: Verleden, 2016 Heden en de Toekomst. 49e Gynaecongres, Eindhoven, the Netherlands. - Laparoscopische visualisatietechnieken bij endometriose. Refereeravond cluster 2016 Obstetrie & Gynaecologie Academisch Medisch Centrum (AMC) en VU medisch centrum (VUmc), Amsterdam,the Netherlands. - Spontaneous Hemoperitoneum in Pregnancy (SHiP) and Endometriosis – A 2015 Dutch Consorted Action. 5de Nederlandse Endometriose Symposium (NVOG Werkgroep Endometriose), Amsterdam, the Netherlands. - Spontaneous Hemoperitoneum in Pregnancy (SHiP) and Endometriosis – an 2015 update of the recent literature. 1st Congress of the Society of Endometriosis and Uterine Disorders (SEUD Congress), Paris, France. - Trial on Uterine Bathing before IVF/ICSI in patients with mild Endometriosis; 2015 TUBIE trial. Voordracht Fertiliteitsclub Noord Holland (FC Noord Holland), Broek in Waterland, the Netherlands. - Pain experience, safety and patient satisfaction during pethidine or patient- 2013 controlled remifentanil analgesia for oocyte retrieval in IVF/ICSI procedures: a randomized controlled trial. Voordracht Fertiliteitsclub Noord Holland (FC Noord Holland), Broek in Waterland, the Netherlands.

Poster presentations - Transanal minimally invasive rectal resection in women with symptomatic deep 2017 endometriosis: description of a novel surgical technique. 13th World Congress on Endometriosis (WCE), Vancouver, Canada. - Spontaneous Hemoperitoneum in Pregnancy (SHiP) and endometriosis. 13th 2017 World Congress on Endometriosis (WCE), Vancouver, Canada.

210 - Validation of Sampson’s theory on retrograde menstruation in endometriosis 2017 patients: a case-control study using MRI. 13th World Congress on Endometriosis (WCE), Vancouver, Canada. - Decidual Bleeding as a cause of spontaneous hemoperitoneum in pregnancy 2017 (SHiP) and risk of preterm birth. 13th World Congress on Endometriosis (WCE), Vancouver, Canada. - The relation between Spontaneous Hemoperitoneum in Pregnancy (SHiP) and 2016 endometriosis - data from a Nationwide Dutch consorted action. 32nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Helsinki, Finland - Laparoscopic advanced Imaging Techniques in Endometriosis therapy: 2015 LITE study. 5de Nederlandse Endometriose Symposium (NVOG Werkgroep Endometriose), Amsterdam, the Netherlands. - Sampsons Theory of Endometriosis tested in Amsterdam by MRI (STEAM): 2015 a case-control study. 5de Nederlandse Endometriose Symposium (NVOG Werkgroep Endometriose), Amsterdam, the Netherlands. - Trial on Uterine Bathing before IVF/ICSI in patients with mild Endometriosis: 2015 TUBIE trial. 5de Nederlandse Endometriose Symposium (NVOG Werkgroep Endometriose), Amsterdam, the Netherlands. - Improved patient satisfaction, less sedation and equal analgesic efficacy for 2012 PCA remifentanil when compared to pethidine during oocyte retrieval in IVF/ ICSI-procedures. 68th Annual Meeting of the American Society for Reproductive Medicine (ASRM), San Diego, USA.

(Inter)nationale conferences attended 56e Gynaecongres, Amersfoort, the Netherlands 2019 54e Gynaecongres, Amersfoort, the Netherlands 2018 53e Gynaecongres, Utrecht, the Netherlands 2018 13th World Congress on Endometriosis (WCE), Vancouver, Canada 2017 49e Gynaecongres, Eindhoven, the Netherlands 2016 European Society of Human Reproduction and Embryology (ESHRE), 32nd Annual 2016 Meeting, Helsinki, Finland 5de Nederlandse Endometriose Symposium (NVOG Werkgroep Endometriose), 2015 Amsterdam, the Netherlands. 1st congress of the Society of Endometriosis and Uterine Disorders (SEUD Congress), 2015 Paris, France American Society for Reproductive Medicine (ASRM) Congress, 68th Annual Meeting, 2012 San Diego, USA

211 Appendices

LIST OF PUBLICATIONS

- Lier MCI, van der Houwen LEE, Mijatovic V. (2021) Endometriosis. Textbook of Obstetrics and Gynaecology. A life course approach. Editor Steegers EAP cs. Houten, Nederland: bohn stafleu van loghum.

- Lier MCI, Vlek SL, Ankersmit M, van de Ven PM, Dekker JJML, Bleeker MCG, Mijatovic V, Tuynman JB. Comparison of enhanced laparoscopic imaging techniques in endometriosis surgery: a diagnostic accuracy study. Surg Endosc. 2020;34:96-104.

- Lier MCI, van der Houwen LEE, Schreurs AMF, van Wely M, Hompes PGA, Cantineau AEP, Schats R, Lambalk CB, Mijatovic V. Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial. Hum Reprod Open. 2019;2019:1-8.

- Lockyer EK, Schreurs A, Lier M, Dekker J, Melgers I, Mijatovic V. Treatment of ovarian endometriomas using plasma energy in endometriosis surgery: effect on pelvic pain, return to work, pregnancy and cyst recurrence. Facts Views Vis Obgyn. 2019;11:49-55.

- van Rijswijk J, van Welie N, Dreyer K, van Hooff MHA, de Bruin JP, Verhoeve HR, Mol F, Kleiman-Broeze KA, Traas MAF, Muijsers GJJM, Manger AP, Gianotten J, de Koning CH, Koning AMH, Bayram N, van der Ham DP, Vrouenraets FPJM, Kalafusova M, van de Laar BIG, Kaijser J, van Oostwaard MF, Meijer WJ, Broekmans FJM, Valkenburg O, van der Voet LF, van Disseldorp J, Lambers MJ, Peters HE, Lier MCI, Lambalk CB, van Wely M, Bossuyt PMM, Stoker J, van der Veen F, Mol BWJ, Mijatovic V. The FOAM study: is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial. BMC Womens Health. 2018;18:64.

- Lier MCI, Mijatovic V; all co-authors. Authors’ reply: Spontaneous haemoperitoneum in pregnancy and endometriosis: a case series. BJOG. 2018;125:392-393.

- Lier MCI, Malik RF, Ket JCF, Lambalk CB, Brosens IA, Mijatovic V. Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis - A systematic review of the recent literature. Eur J Obstet Gynecol Reprod Biol. 2017;219:57-65.

- Lier MCI, Malik RF, van Waesberghe JHTM, Maas JW, van Rumpt - van de Geest DA, Coppus SF, Berger JP, van Rijn BB, Janssen PF, de Boer MA, de Vries JIP, Jansen FW, Brosens IA, Lambalk CB, Mijatovic V.Spontaneous Hemoperitoneum in Pregnancy (SHiP) and Endometriosis: A Case Series. Brit J Obstet Gynaecol 2017;124:306-312.

212 - Vlek SL, Lier MCI, Koedam TWA, Melgers I, Dekker JJML, Bonjer JH, Mijatovic V, Tuynman JB. Transanal minimally invasive rectal resection for deep endometriosis; a promising technique. Colorectal Dis. 2017;19:576-581.

- Lier MCI, Brosens IA, Mijatovic V, Habiba M, Benagiano G. Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth. Gynecol Obstet Invest. 2017;82:313-321.

- Vlek SL, Lier MCI, Ankersmit MA, Ket JCF, Dekker JJML, Mijatovic V, Tuynman JB.Laparoscopic imaging techniques in endometriosis therapy - a systematic review. J Minim Invasive Gynecol. 2016 Sep-Oct;23(6):886-892.

- Brosens IA, Lier MC, Mijatovic V, Habiba M, Benagiano G. Severe spontaneous hemoperitoneum in pregnancy may be linked to in vitro fertilization in patients with endometriosis: a systematic review. Fertil Steril. 2016;106:692-703.

- Vlek SL, Lier MCI, Dekker JJML, Melgers I, Mijatovic V, Tuynman JB. Minimaal invasieve transanale resectie bij diepe endometriose van het rectum. NTOG. 2016;129:239–244.

- Lier MCI, RF Malik, van Waesberghe JHTM, Maas JW, van Rumpt - van de Geest DA, Coppus SF, Berger JP, van Rijn BB, Janssen PF, de Boer MA, de Vries JIP, Jansen FW, Brosens IA, Lambalk CB, Mijatovic V. Spontaneous Hemoperitoneum in Pregnancy (SHiP) en Endometriose – Verleden, Heden en de Toekomst. NTOG. 2016;129:245–249.

- Vlek SL, Lier MCI, Ankersmit M, Ket JCF, Dekker JJML, Mijatovic V, Tuynman JB. Laparoscopische visualisatietechnieken voor peritoneale endometriose. NTOG. 2016;129:250–255.

- Dreyer K, Lier MCI, Emanuel MH, Twisk JWR, Mol BWJ, Schats R, Hompes PGA, Mijatovic V. Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT. Hum Reprod. 2016;31:2005-2016.

- Lier MC, Douwenga WM, Yilmaz F, Schats R, Hompes PG, Boer C, Mijatovic V. Patient-Controlled Remifentanil Analgesia as Alternative for Pethidine with Midazolam During Oocyte Retrieval in IVF/ICSI Procedures: A Randomized Controlled Trial. Pain Pract. 2015;15:487-495.

- Lier MCI, van der Houwen LEE, van Groeningen I, van Waesberghe JHTM, Hompes PGA, Mijatovic V. Spontane abdominale bloeding in de zwangerschap: SHiP. NTOG. 2014;127:448 – 451.

213 Appendices

LIST OF CO-ATHORS

M. Ankersmit MD, PhD Department of Surgery, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

J.P. Berger MD Department of Obstetrics and Gynaecology, Bronovo Hospital, The Hague, the Netherlands.

M.C.G. Bleeker MD, PhD Department of Pathology, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

M.A. de Boer MD, PhD Department of Obstetrics and Gynaecology, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

A.E.P. Cantineau MD, PhD Department of Reproductive Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

G. Benagiano MD, PhD Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy.

I.A. Brosens MD, PhD Leuven Institute for Fertility and Embryology, Leuven, Belgium.

S.F. Coppus MD, PhD Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands.

J.J.M.L. Dekker MD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

K. Dreyer MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

214 M. Habiba PhD Department of Obstetrics and Gynaecology, Leicester Royal Infirmary, University Hospitals of Leicester, Leicester, United Kingdom.

P.G.A. Hompes MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

L.E.E. van der Houwen MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

F.W. Jansen MD, PhD Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.

P.F. Janssen MD, PhD Department of Obstetrics and Gynaecology, St. Elisabeth Hospital, Tilburg, the Netherlands.

Johnson N.P. MD, PhD Robinson Research Institute, University of Adelaide, South Australia. Repromed Auckland and Auckland Gynaecology Group, Auckland, New Zealand. The University of Auckland, Auckland, New Zealand.

Ket J.C.F. Medical Library, VU University Amsterdam, Amsterdam, the Netherlands.

Kuchenbecker W. MD, PhD Department of Reproductive Medicine, Isala, Zwolle, the Netherlands.

C.B. Lambalk MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

J.W. Maas MD, PhD Department of Obstetrics and Gynaecology, Maxima Medical Center, Veldhoven, the Netherlands.

215 Appendices

R.F. Malik MD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

V. Mijatovic MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

B.W. Mol MD, PhD Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia.

H. Özcan MD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

B.B. van Rijn MD, PhD Department of Obstetrics, Wilhelmina Children’s Hospital Birth Centre, University Medical Centre Utrecht, Utrecht, the Netherlands. Academic Unit Human Development and Health, Institute for Life Sciences, University of Southampton, Southampton, UK.

D.A. van Rumpt-van de Geest MD Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Delft, the Netherlands.

R. Schats MD, PhD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

A.M.F. Schreurs MD Department of Reproductive Medicine, Amsterdam University Medical Center - VU University Amsterdam, Amsterdam, the Netherlands.

J.B. Tuynman MD, PhD Department of Surgery, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

216 van de Ven P.M. PhD Department of Epidemiology and Biostatistics, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

Vandekerckhove F. MD, PhD Department of Reproductive Medicine, Ghent University Hospital, Gent, Belgium.

Verhoeve H.R. MD, PhD Department of Reproductive Medicine, OLVG, Amsterdam, the Netherlands.

S.L. Vlek MD Department of Surgery, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

J.I.P. de Vries MD, PhD Department of Obstetrics and Gynaecology, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

J.H.T.M. van Waesberghe MD, PhD Department of Radiology, Amsterdam University Medical Center – VU University Amsterdam, Amsterdam, the Netherlands.

M. van Wely PhD Department of Reproductive Medicine, Amsterdam University Medical Center - University of Amsterdam, Amsterdam, the Netherlands.

217 Appendices

DANKWOORD

Het is klaar! Wat een feest om het eindresultaat hier nu gebundeld voor me te zien liggen! Het was een intensief, maar ook heel bijzonder traject. Dit boekje was er zeker niet geweest zonder de hulp van velen. Hieronder een aantal die ik in het bijzonder wil bedanken.

Allereerst alle vrouwen die hebben deelgenomen aan de onderzoeken. Dank voor jullie medewerking en vertrouwen!

Prof.dr. V. Mijatovic, beste Velja. Je stond aan het begin van mijn wetenschappelijke carrière in 2010, toen ik als onderzoeksstudent begon op de afdeling Voortplantingsgeneeskunde (VPG). Enkele jaren later begonnen we samen aan dit promotietraject, jij aanvankelijk als mijn copromoter, maar sinds kort als mijn eerste promotor. Van harte gefeliciteerd! Bedankt voor je motiverende woorden, snelle reactietijd, persoonlijke interesse en de ruimte die je gaf om mezelf te ontwikkelen. Onze reis naar Vancouver, de vele etentjes, autoritten naar België en de prachtige fles champagne voor mijn huwelijk zal ik nooit vergeten!

Prof.dr. C.B. Lambalk, beste Nils. Bedankt voor je begeleiding van dit promotietraject! Ook al liet je reactie soms even op zich wachten, jouw creativiteit, bevlogenheid en kritische blik zijn bewonderingswaardig! Jouw finishing touch heeft vele van mijn manuscripten naar een hoger niveau getild. Bedankt daarvoor!

Dr. P.G.A. Hompes, beste Peter. Alhoewel je al een tijdje bent afgezwaaid, wil ik je hier toch bedanken. Zonder jou had ik hier niet gestaan. Je nam me aan als ANIOS bij de VPG en vanuit daar is het balletje gaan rollen. Bedankt voor de lunches en Long Johns op dinsdagmiddag, de wijze lessen die je met hebt geleerd over boten en vliegtuigen en je begeleiding tijdens mijn eerste wetenschappelijke congres in San Diego.

Geachte leden van de leescommissie, prof.dr. C.J.M. de Groot, prof.dr. C. Tomassetti, prof.dr. F.W. Jansen, prof.dr. K.W.M. Bloemenkamp, prof.dr. A.W. Nap en dr. E. Moll. Hartelijk dank voor de tijd en moeite die jullie hebben gestoken in de beoordeling van mijn manuscript. Ik kijk ernaar uit om het te verdedigen.

Alle co-auteurs: dank voor jullie inzet, fijne samenwerking en kritische commentaren.

Dank ook aan alle lokale onderzoekers en andere betrokkenen uit deelnemende klinieken. Zonder jullie inzet was dit resultaat er niet geweest.

Gynaecologen, arts-assistenten, klinisch verloskundigen, verpleegkundigen, arts- onderzoekers, IVF-artsen, embryologen en medewerkers van het Amsterdam

218 Universitair Medisch Centrum, locatie VUmc. Bedankt voor de leerzame en fijne periode als arts-assistent en arts-onderzoeker in zowel de kliniek, op de poli VPG als in het IVF-centrum. Sinds augustus terug als AIOS in het warme VU-nest en wat voelt het alweer snel vertrouwd!

Lieve GYNAIKA’s: lieve Annefleur, Anke, Anouk, Eva, Henrike, Inge, Jorine, Joukje, Marjolein, Mirte, Nicole, Sanne en Wieke. Jullie hebben mijn onderzoekstijd tot een waar feest gemaakt en wat ben ik dankbaar voor de waardevolle vriendschappen die hieruit zijn voortgekomen. De vele etentjes, borrels, kroketlunches en schrijfweekenden in Zeeland waren onbetaalbaar. Gelukkig is de wintersport inmiddels verheven tot een (bijna) jaarlijkse traditie. GYNAIKA’s voor het leven!

Lieve VPG’tjes, lieve Henrike, Joukje en Mirte. Wat fijn om samen op te trekken in het onderzoek, de vele wetenschapsbesprekingen waren met jullie toch een stuk gezelliger! Lieve Lisette, bedankt voor de rijdende endometriose-onderzoekstrein waar ik deels op mee kon liften. Lieve Anneke, bedankt voor het overnemen van mijn nog lopende onderzoeken en het afronden van de TUBIE. Heel veel succes met het voortzetten van de COPIE en je eigen promotietraject.

Lieve Endonerds, Anke, Marjolein, Yolande, Eva en Kim. Bedankt voor de leerzame (literatuur)besprekingen, gezellige lunches en diners aan het begin van mijn VPG- carrière. Een goed begin is tenslotte het halve werk!

Lieve Yvonne, lieve zuster. Ondanks de vele extra kilo’s die ik ben aangekomen sinds ik jou ken, was mijn tijd bij de VPG niet hetzelfde geweest zonder alle dropjes, koekjes en taartjes die jij mij tussendoor toestopte. Bedankt voor je zorgzaamheid, humor en gezelligheid. Ik hoop dat er nog vele etentjes met elkaar volgen, ik neem mijn Tupperware bakjes alvast mee!

Beste Madeleine, bedankt voor je hulp, praktische adviezen en Engelse drop tijdens mijn promotietijd. Sorry dat ik de pot zo vaak leeg achter heb gelaten!

Lieve gynaecologen, arts-assistenten, verpleegkundigen en medewerkers van de afdeling obstetrie en gynaecologie van het OLVG, locatie West. Bedankt voor de heerlijke 3 jaar die ik bij jullie mocht werken. Wat zijn jullie een prachtig team en wat heb ik mij altijd welkom en gewaardeerd gevoeld. Lieve Etelka, bedankt dat jij er als opleider altijd voor mij was en het vertrouwen dat je in mij had. Zonder de schrijftijd die ik heb gekregen in het OLVG was dit boekje er nu nog steeds niet geweest. Ik vind het een eer en heel bijzonder dat je onderdeel bent van mijn leescommissie. Dankjewel! Lieve Kim, wat ben ik blij dat ik jou heb getroffen als opleidingsmaatje in het OLVG. Helaas zijn onze wegen nu even gesplitst, maar ik hoop nog vaak koffie met je te drinken en te spuien over onze toekomst!

219 Appendices

Lieve paranimfen: Lieve Marly, vanaf de eerste minuut van onze geneeskunde-opleiding zijn we onafscheidelijk. Aan een blik hebben we vaak al genoeg. Je bent de liefste en meest zorgzame vriendin die ik ken. Wat ben ik dankbaar voor onze onvoorwaardelijke vriendschap. Ik vind het heel bijzonder dat je ook vandaag weer aan mijn zijde staat en ik kan niet wachten op de vele mooie momenten die wij, samen met onze mannen, nog gaan beleven!

Lieve Kim, kamergenootje vanaf het eerste uur. Bedankt voor je enthousiasme, inspirerende gedrevenheid en gezelligheid. Wat voor vragen ik ook had, ik kon altijd bij je terecht. De (cappuccino en praliné) paaseieren waren bij ons niet aan te slepen en je manier van enveloppen dichtlikken zal ik nooit vergeten. Wat ben ik blij dat je vandaag ook naast mij staat!

Lieve Stef en Steef, dat het MFVU bestuur zou zorgen voor zulke hechte en onvoorwaardelijke vriendschappen had ik nooit gedacht. Wat hebben we al veel meegemaakt sindsdien. Bedankt dat jullie er altijd zijn! Ik heb grote bewondering hoe jullie alles altijd zo makkelijk lijkt af te gaan, maar ik weet dat jullie er keihard voor werken. Van Bonaire tot Milaan en Amsterdam, het leven met jullie is een feest! Laten we snel weer een weekendje weg gaan!

Lieve Elke, Char, Suuz (& Mar); Very BadEendjes. Bedankt voor jullie bijzondere vriendschap, die ooit is ontstaan op het hockeyveld. Waar ter wereld we ons ook begeven, we weten elkaar altijd weer te vinden en de draad op te pakken alsof we elkaar gisteren nog hebben gezien!

Lieve Brakke Brunchers, lieve Pim, Marly, Marco, Odette, Lucas, Feline, Nick, Thessa, Roel, Denise, Josser en Marjolein. Dank dat ik deel uit mag maken van deze bijzondere vriendengroep. Ondanks alle gezinsuitbreidingen treffen we elkaar bijna maandelijks voor een brakke zondagsbrunch. Bedankt voor deze fijne momenten van ontspanning en gezelligheid!

Lieve Leo en Pieter, opvanghuize Van Tuyll. Bedankt voor jullie steun in moeilijke tijden, maar ook voor jullie gezelligheid daarbuiten.

Lieve Marianne en Piet, lieve schoonouders. Bedankt voor al jullie hulp en betrokkenheid bij ons gezin. Zo fijn dat we altijd bij jullie mogen aankloppen. Lieve Bas, Denise en Rob bedankt voor de gezellige avonden in de Beemster.

Lieve Mart, kleine grote broer. Wat ben ik trots op hoe je de afgelopen jaren bent gegroeid tot de zelfverzekerde man die je nu bent. Ik heb bewondering voor je enorme

220 communicatieve vaardigheden, ik ken niemand met zoveel vrienden als jij! Bedankt voor je betrokkenheid, interesse en dat je zo’n lieve oom bent voor Teun.

Lieve Pap, bedankt voor je steun en oeverloze vertrouwen. Zonder had ik hier nu niet gestaan. Je kocht ooit een fles champagne omdat ik mijn eerste (en enige) onvoldoende haalde op de middelbare school, maar ik hoop dat we op dit resultaat ook een goed glas gaan drinken. Bedankt ook voor al je hulp en correcties van de Engelse taal, je bent waarschijnlijk de enige die dit hele boek heeft doorgelezen! Lieve Marianne, bedankt dat je er altijd voor papa bent. Lieve Annette en Mo, lieve tantes, bedankt voor jullie luisterend oor en hulp wanneer dat nodig was.

Lieve Mam, het is moeilijk om je in een paar zinnen te bedanken. Je hebt me altijd onvoorwaardelijk gesteund en vrijgelaten in de keuzes die ik maakte. Vanaf het begin ben je betrokken geweest bij mijn promotietraject, waarbij je het zelfs voor elkaar wist te krijgen om binnen te glippen bij het SEUD congres in Parijs om mijn eerste wetenschappelijk presentatie bij te wonen. Ik geniet enorm van de gezelligheid en de warme plek die jij en Michael creëren in Utrecht. Samen met Mart, Djoeke, Dirk, Hidde, Tom en Teun hebben we al mogen genieten van vele heerlijke avonden (en het jaarlijkse paaseieren zoeken). Bedankt dat jullie altijd voor ons klaarstaan! Lieve Cros, je bent de liefste hond die ik ken en Teun kan niet wachten om samen met je te gaan ballen!

Allerliefste Tom, ik ben jou het meeste dank verschuldigd van iedereen. Wat ben ik gelukkig met jou in mijn leven. Bedankt voor je onvoorwaardelijke liefde, eindeloze steun en opbeurende woorden als ik er even helemaal doorheen zat. Wat is het bijzonder om samen met Teun de wereld te ontdekken. Ik kan niet wachten op wat de toekomst ons allemaal nog gaat brengen. Lieve Teun, je bent het grootste cadeau wat ons ooit is overkomen, met jou om ons heen is de rest maar relatief! Ik hou van jullie!

221 Appendices

OVER DE AUTEUR

Marit Lier werd geboren op 9 augustus 1988 in Nieuwegein, als oudste dochter van Guy en Yontie. 4,5 jaar later werd haar broertje Mart geboren. Marit groeide op in Houten. Na het behalen van haar gymnasiumdiploma aan het Openbaar Zeister Lyceum startte zij haar studie Geneeskunde aan de Vrije Universiteit in Amsterdam. Een intensieve, maar gezellig studententijd volgde, waarin Marit verschillende bestuurlijke functies beklede binnen de studievereniging MFVU en de Studentenraad. Na het behalen van haar bachelor werkte Marit drie maanden als vrijwilliger in een ziekenhuis in Arusha, Tanzania.

In 2010 begon Marit als wetenschappelijke stage student op de afdeling Voortplantingsgeneeskunde van het VU medisch centrum (VUmc) aan een onderzoek naar de pijnbestrijding bij de eicelpunctie, waarna de interesse voor de gynaecologie en obstetrie was gewekt. Na het afronden van haar coschappen heeft Marit in 2013 als arts-assistent niet in opleiding klinische ervaring opgedaan op de poli Voorplantingsgeneeskunde van het VUmc. Na een jaar startte zij in 2014, onder begeleiding van Velja Mijatovic en Nils Lambalk, het promotietraject wat leidde tot deze dissertatie.

In september 2017 is Marit begonnen als arts-assistent obstetrie en gynaecologie in het OLVG West, waar zij na een half jaar met veel enthousiasme mocht beginnen aan de opleiding tot gynaecoloog aan het VU Medisch Centrum (opleider dr. A.W. Valkenburg – van den Berg). Het eerste deel van haar opleiding heeft zij gevolgd in het OLVG West (opleider dr. E. Moll). Sinds augustus 2020 is Marit terug als arts-assistent in het VUmc.

Marit woont samen met haar man Tom Schoorl en zoon Teun (03-2019) in Badhoevedorp. Binnenkort volgt er gezinsuitbreiding.

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