live birth using vitrified–warmed oocytes in invasive ovarian cancer: case report and literature...

Reproductive BioMedicine Online (2014) xxx, xxx–xxx

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REVIEW

Live birth using vitrified–warmed oocytesin invasive ovarian cancer: case reportand literature review

http://dx.doi.org/10.1016/j.rbmo.2014.02.0101472-6483/ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Alvarez, M et al. Live birth using vitrified–warmed oocytes in invasive ovarian cancer: case report and litreview. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.02.010

Manuel Alvarez a,*, Miquel Sole a, Marta Devesa a, Rafael Fabregas b,Montserrat Boada a, Rosa Tur a, Buenaventura Coroleu a, Anna Veiga a,c,Pedro N Barri a

a Service of Reproductive Medicine, Department of Obstetrics, Gynaecology and Reproduction, University Hospital QuironDexeus, Barcelona, Spain; b Service of Oncological Gynaecology, Department of Obstetrics, Gynaecology and Reproduction,University Hospital Quiron Dexeus, Barcelona, Spain; c Center of Regenerative Medicine (CMR [B]), Barcelona, Spain* Corresponding author. E-mail address: [email protected] (M Alvarez).

Abstract This article rep

Dr Manuel Alvarez graduated from the Autonoma University of Madrid (Faculty of Medicine) in 1993. He becamea specialist in Gynaecology and Obstetrics at the Institut Universitary Dexeus (Barcelona) where he is developinghis professional career. He is an active member of the Service of Reproductive Medicine as a senior MD and he ismainly focused on monitoring, IVF puncture and embryo transfer. He also holds the position of Secretary of theTeaching Committee at University Hospital Quiron Dexeus, co-operating with programmes for improving thequality and efficiency of future specialists in Obstetrics and Gynaecology.

orts the live birth of a healthy newborn using vitrified–warmed oocytes in a young patient with invasivemucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cyclesof ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One yearlater, a transfer of two embryos was performed after insemination of warmed oocytes. Eighteen days after the transfer, she under-went a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in theuterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was con-firmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthyboy weighing 2650 g. As far as is known, this is the first live birth reported through vitrified–warmed oocytes in a patient with inva-sive ovarian cancer. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases

of ovarian cancer, controversial issues are discussed. RBMOnline

ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: fertility preservation, fertility-sparing surgery, heterotopic pregnancy, ivf in cancer patients, ovarian cancer, oocytevitrification

erature

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http://dx.doi.org/10.1016/j.rbmo.2014.02.010



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2 M Alvarez et al.

Introduction

Cancer continues to be amajor problem inWestern countriesnot only in terms of survival but also in terms of loss in child-bearing potential. Fortunately prospects have improved withthe arrival of new techniques for oocyte cryopreservationand new approaches to therapeutic strategies for oncologicalpatients. These advances have raised the possibility of seek-ing pregnancy in oncological patients. Nowadays, there is noevidence that fertility preservation techniques lead toreduced success rates in the treatment of cancer (Jerussand Woodruff, 2009). Also, fertility preservation would beof psychological benefit to these patients (Letourneauet al., 2012) with the fertility preservation consultation pro-viding a useful source of information. According to Kim et al.(2013), 73% of patients made up their mind about treatmentafter this consultation.

Published results using vitrified–warmed oocytes in younginfertility patients and oocyte donors (Cobo et al., 2011;Rienzi et al., 2012) have made oocyte vitrification one ofthe strategies of choice for fertility preservation, althoughthere is a trend towards combining several strategies in ordertomaximize chances of success (Gonzalez et al., 2011; Martı-nez et al., 2013). Fertilization and pregnancy rates are simi-lar to IVF/intracytoplasmic sperm injection with freshoocytes, and no increase in chromosomal abnormalities,birth defects or developmental deficits have been describedin children born from cryopreserved oocytes (Chian et al.,2008). So, the Practice Committee of the American Societyfor Reproductive Medicine (2013) recommends oocyte pres-ervation as one of the options, with appropriate counselling,in patients with cancer and high risk for infertility and saysthat ‘evidence indicates that oocyte vitrification should nolonger be considered experimental’. Unfortunately referralsof oncological patients to fertility specialists are below 50%according to Quinn et al. (2009), despite the recommenda-tions of scientific societies and committees (Kim et al., 2012;Lee et al., 2006; Martınez et al., 2013; Practice Committee ofthe American Society for Reproductive Medicine, 2013).

As far as is known, no case of a live birth has beendescribed using oocyte vitrification as a strategy for fertilitypreservation prior to oncological surgery for invasiveovarian cancer, although there is a recommendation forfertility-sparing surgery in early stages of ovarian cancer(Kashima et al., 2013; Morice et al., 2011). This reportdescribes a live birth using vitrified–warmed oocytes andfertility-sparing surgery in a woman with invasive ovariancancer (stage Ic). Controversial issues are subsequentlyreviewed and discussed.

Case report

A 28-year-old patient attended this study centre for a sec-ond opinion in January 2010. She had a laparoscopic leftadnexectomy in another centre because of a 17-cm adnexalcystic mass under ultrasound scan. Tumour markers werenegative at that time. Pathology was consistent with aninvasive mucinous carcinoma with foci of borderline mucin-ous carcinoma.

Fertility preservation was authorized by the Committeeof Gynecological Oncology according to patient’s desire,

Please cite this article in press as: Alvarez, M et al. Live birth using vitrifiedreview. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.101

age, the histological diagnosis and the prognosis of the dis-ease (surgical stage Ic of ovarian cancer). The patient wasimmediately referred to the Service of Reproductive Medi-cine for oocyte vitrification prior to completing surgery.The patient’s ovarian reserve was assessed by antral folliclecount on ultrasound (eight follicles) and anti-Mullerian hor-mone (2.1 ng/ml).

Ovarian stimulation was started under a multiple doseflexible gonadotrophin-releasing hormone antagonist proto-col (cetrorelix 0.25 mg/ml; Cetrotide; Merck-Serono, Spain)and 225 IU/day recombinant FSH (Gonal F; Merck-Serono).Ovulation was triggered with 250 lg recombinant humanchorionic gonadotrophin (Ovitrelle; Merck-Serono) whenthe two leading follicles were �17 mm. Follicular aspirationtook place after 36 h and five oocytes were retrieved. FourMII oocytes were immediately vitrified as previouslydescribed by Kuwayama et al. (2005). A second ovarianstimulation cycle was performed 1 month later with an ini-tial dose of 300 IU/day of recombinant FSH due to the lownumber of vitrified oocytes. Fourteen oocytes wereretrieved and 10 MII were vitrified as previously described.

Patient underwent surgical treatment in the study centrein July 2010 by means of laparoscopic right adnexectomy,appendectomy and pelvic and aortic lymphadenectomy aswell as omentectomy. Thus the uterus was preserved in thissurgery. The histopathological study was normal and with nometastatic invasion in 26 lymph nodes. The patient did notrequire subsequent treatment with radio- or chemotherapy.

Fertility preservation and the later use of the oocytes forIVF were both approved by the Committee of GynecologicalOncology (reference no. CGOM27012010/2.4, approved 27January 2010) and the Institutional Review Board (referenceno. CIOG01092010/03, approved 1 September 2010) of Uni-versity Hospital Quiron Dexeus. The patient gave her writ-ten consent for these processes.

One year later, tumour markers were negative and theCommittee of Gynecological Oncology authorized the useof vitrified oocytes. Hormonal replacement therapy forendometrial preparation was prescribed according to theprotocol described previously (Martınez et al., 2006).Warming of eight oocytes was performed in accordance withthe protocol described by Kuwayama et al. (2005). Sevenoocytes survived and were inseminated with the partner’ssemen using intracytoplasmic sperm injection after 2 h ofculture in IVF medium (Vitrolife, Sweden). Normal fertiliza-tion of seven oocytes was assessed at 18 ± 2 h. On the fol-lowing day (day 2), two optimal-quality embryos weretransferred under ultrasound guidance (Coroleu et al.,2002). On day 3 of development (68 ± 2 h), two optimal-quality embryos were cryopreserved for future attempts.

Serum b-human chorionic gonadotrophin assayed 12 daysafter embryo transfer was 218 IU/l. The patient presentedat her home hospital 8 days later with abdominal pain andvaginal bleeding. A laparotomy was performed with theclinical suspicion of heterotopic pregnancy since thepatient’s haemoglobin concentrations had decreased from14 g/dl to 10.7 g/dl and an ultrasound scan demonstratedthe presence of haemoperitoneum and an intrauterinegestational sac. The review of the abdominal cavity showeda right cornual ectopic pregnancy in the uterus. A wedgeresection was performed along with interruptedhaemostatic sutures for uterine closure. Four days after

–warmed oocytes in invasive ovarian cancer: case report and literature6/j.rbmo.2014.02.010


Table

1Live

birthsreportedin

cance

rpatients

whopreservedfertilitythrough

oocyte

cryo

preservation.

xTyp

eof

malign

ancy

Age

atoocyte

cryo

preservation

(years)

Cryopreservationtech

nique

Cryopreserved

oocytes

Storage

time

(years)

Pregn

ancy

Live

births

Weeks

of

gestation

Birthweight

(g)

Kim

etal.(2011

)Chronic

mye

loid

leuka

emia

22

Electronmicroscopygrid

(vitrifica

tion)

79

Single

135

2410

GarcıaVelascoetal.

(2013

)Non-H

odgk

inlymphoma

31

Cryotop(vitrifica

tion)

42

Single

139

3440

Yangetal.(200

7)Hodgk

inlymphoma

27

Slow

freezing

136

Single

137

3062

Sanch

ez-Se

rran

oetal.

(201

0)BreastCan

cer

36Ova

rian

tissuecryo

preservation/

grafting+Cryotop(vitrifica

tion)

162

Twin

234

1650

and

1830

This

study

Inva

sive

mucinous

ova

rian

carcinoma

(stage

Ic)

28Cryotop(vitrifica

tion)

141

Heterotopic

138

2650

Live birth using vitrified–warmed oocytes in ovarian cancer 3


surgery, a vaginal ultrasound was performed confirming aviable intrauterine pregnancy according to 5 weeks ofamenorrhoea. A healthy boy weighing 2650 g was born byelective Caesarean section at 38 weeks of gestation.

The patient continues her follow up and she is free fromdisease 36 months after diagnosis.

Discussion

Results concerning the efficiency and safety of vitrified–warmed oocytes, as well as the absence of correlation withhigher rates of adverse perinatal outcomes (Noyes et al.,2009; Rienzi et al., 2012), allow the possibility of vitrifyingoocytes in patients who are obliged for medical reasons todelay motherhood. Success rates must be extrapolated fromother populations as only a few live births from oocyte vit-rification in cancer patients have been reported (Table 1). Atwin pregnancy was achieved in a breast cancer patientcombining ovarian tissue cryopreservation/grafting and suc-cessive ovarian stimulation cycles for oocyte vitrification(Sanchez-Serrano et al., 2010). Two additional single livebirths have been reported after vitrifying oocytes in twocases of blood malignancies (Garcıa Velasco et al., 2013;Kim et al., 2011). With regard to the ovary, Porcu et al.(2008) has reported a twin pregnancy and live birth afteroocyte cryopreservation in a borderline ovarian tumourusing a slow freeze–rapid thaw protocol. As far as is known,no case of oocyte vitrification as a strategy for fertility pres-ervation in invasive ovarian cancer and live birth has beenreported. The number of reported cases is small as currentlyonly a few women have sought treatment using their cryo-preserved oocytes. In a recent report, Garcıa Velascoet al. (2013) described that only four of 340 cancer patients(mainly breast cancer patients) who had oocytes vitrified forfertility preservation had returned for treatment with theseoocytes. Many different reasons could justify that low rateof use (no partner, lack of oncologist authorization, difficul-ties in deciding to become mother).

Although fertility preservation is not the standardapproach to invasive epithelial ovarian cancer, fertility-sparing surgery is an option in young patients who wish topreserve their childbearing potential, therefore it shouldbe ensured that patients are fully informed of the optionsand that the subsequent follow up is properly fulfilled. Cur-rent literature indicates that the optimal stages for fertility-sparing surgery are stage Ia with favourable histology(mucinous, serous, endometrioid or mixed histology) andgrade 1 or 2, even without adjuvant chemotherapy (Kashimaet al., 2013; Morice et al., 2011). Overall survival rates inthe case of iatrogenic stage Ic (due to intraoperative cystrupture), such as the case reported, are comparable withthose for stage Ia, but not with biological stage Ic disease(due to malignant cells in the Douglas cytology or surfaceinvolvement) (Kajiyama et al., 2010). One option in iatro-genic stage Ic could be a bilateral adnexectomy and uteruspreservation, which would permit future fertility treatmentthrough oocyte donation or even use of the patient’s ownoocytes if they were vitrified prior to the adnexectomy(Morice et al., 2011). In the reported case, because theprobability of involvement for mucinous tumour in theremaining ovary was extremely low according to literature



4 M Alvarez et al.

(Zanetta et al., 1997) and the ultrasound scan was normal,ovarian stimulation for oocyte vitrification was performedprior to fertility-sparing surgery.

Careful staging of the disease must be performedthrough an obligatory systemic lymphadectomy, avoidingthe possibility of understaging in these patients. In this casethere was no evidence of metastasis in the histopathologicalstudy of pelvic and aortic lymphadenectomy. So it is con-cluded that fertility-sparing surgery in this case of earlystage epithelial ovarian cancer was safe and viable topreserve childbearing potential although there are no ran-domized trials and clinical experience is limited to retro-spective case series (Kashima et al., 2013).

Another point of discussion is the use of ovarian stimula-tion in ovarian cancer, although it is not generally hor-mone-dependent. Concerns regarding oestradiolconcentrations and subsequent pregnancy hormone profilesare an extrapolation from breast cancer fears (Zhang et al.,2005). Currently there is no evidence of an adverse effect ofIVF treatment and pregnancy on the course of borderlineovarian tumours (Fasouliotis et al., 2004) and there is littleinformation in the literature about ovarian stimulation inpatients with invasive epithelial ovarian cancer (Abu-Musaet al., 2008; Kitagima et al., 2007; Zhang et al., 2005). How-ever, IVF did not appear to be associated with an elevatedovarian cancer risk when the confounding effect of infertil-ity was neutralized in studies allowing such comparisons(Siristatidis et al., 2013). Taking these facts into account,a standard recombinant FSH dose (225 UI/day) was estab-lished with the aim of only one ovarian stimulation. As onlyfour oocytes were vitrified in this first attempt, a secondovarian stimulation was performed by increasing therecombinant FSH dose to 300 UI/day. In fact, many authorsconsider cancer patients as low responders (Domingo et al.,2012; Friedler et al., 2012). In line with this, ovulation trig-gering with gonadotrophin-releasing hormone agonists wasnot considered. Nevertheless it is important to bear in mindthat, after the ovarian stimulation cycles, complete onco-logical surgery was performed with uterus preservation.

The number of warmed oocytes was fully agreed with thepatient according to this study centre’s reported resultswith vitrified oocytes: 85.6% oocyte survival rate afterwarming, 78.2% fertilization rate of the survived ooctyesand 68.2% ongoing embryos (Sole et al., 2013). As a conse-quence of this, two optimal embryos were transferred andonly two embryos were cryopreserved.

Assisted reproduction may be used in order to optimizethe chances of fertility preservation and pregnancy throughembryo, ovarian tissue and/or oocyte cryopreservation.Other options which can be considered include the combina-tion of immature egg retrieval followed by in-vitro matura-tion (IVM) and oocyte vitrification (Huang et al., 2007), orcombination of ovarian tissue freezing with retrieval ofimmature eggs followed by IVM and oocyte vitrification(Huang et al., 2008, 2010) since IVM and oocyte vitrificationcan also lead to live births (Chian et al., 2009).

Finally, the exceptional occurrence of a heterotopicpregnancy in this case should not be overlooked. Vigilanceover the adnexal regions is of paramount importance inIVF patients despite the confirmation of an intrauterinepregnancy (Mancini et al., 2011).


In conclusion, the continuous advances in assisted repro-duction together with greater knowledge of the oncologicalphysiopathology, making treatments even more personal-ized and conservative, have obviously changed the possibil-ities for oncological patients to fulfil their desires for futurepregnancy. It is of utmost importance to refer thesepatients to assisted reproduction centres to inform themof the possibility of setting up different strategies for fertil-ity preservation according to their age, disease and timeavailable until the beginning of their oncological treatment.When the possibility exists and there is time enough to carryout an ovarian stimulation cycle, oocyte vitrification is cur-rently considered the best option. One clear example of thelatter is this case where, in spite of the complexity of theinitial situation, the patient achieved her goal of becominga mother after invasive ovarian cancer by undergoing ovar-ian stimulation and oocyte vitrification prior to fertility-sparing surgery.

Acknowledgements

This work was performed under the auspices of ‘Catedrad’Investigacio en Obstetricia I Ginecologıa’ of the Depart-ment of Obstetrics, Gynaecology and Reproduction, Univer-sity Hospital Quiron Dexeus, Universidad Autonoma deBarcelona. The authors wish to thank Grupo HospitalarioQuiron Zaragoza for all the obstetric follow up in thispatient.

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Declaration: The authors report no financial or commercialconflicts of interest.

Received 26 July 2013; refereed 7 February 2014; accepted 13February 2014.











live birth using vitrified–warmed oocytes in invasive ovarian cancer: case report and literature...

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