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Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Comprehensive Cancer Center ER-EMN, 91054 Erlangen, Germany
Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Comprehensive Cancer Center ER-EMN, 91054 Erlangen, Germany
Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Comprehensive Cancer Center ER-EMN, 91054 Erlangen, Germany
Department of Obstetrics and Gynecology, Freiburg University Hospital, Albert-Ludwigs University of Freiburg, 79106 Freiburg, Germany (now Mainz University Hospital, Johannes Gutenberg University of Mainz, 55122 Mainz, Germany)
Department of Obstetrics and Gynaecology, Heidelberg University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany (B.T. now Department of Gynecological Endocrinology and Reproductive Medicine, University of Innsbruck, 6020 Innsbruck, Austria)
Department of Obstetrics and Gynaecology, Heidelberg University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany (B.T. now Department of Gynecological Endocrinology and Reproductive Medicine, University of Innsbruck, 6020 Innsbruck, Austria)
Fertility-preserving measures are becoming important for patients receiving oncological treatment. One method involves cryopreservation of ovarian tissue and transplanting it when treatment is completed. We report complications resulting from surgical and fertility medicine, and the results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. A survey using a structured questionnaire was conducted among the FertiProtekt network centres between November 2015 and June 2016. The analysis included surgical techniques used to remove and transplant ovarian tissue, surgical complications and results. Laparoscopic removal and transplantation of ovarian tissue have a low risk of complications. Surgical complications occurred in three of the network's 1373 ovarian tissue removals (n = 1302) and transplantations (n = 71); two complications (0.2%) occurred during removal and one during transplantation. Menstruation resumed in 47 out of 58 women (81%) who underwent ovarian tissue transplantation. Hormonal activity occurred in 63.2% of transplantations with a follow-up of 6 months or over. Sixteen pregnancies occurred in 14 patients, with nine births. The risks and complications of removal and transplantation of ovarian tissue are similar to those of standard laparoscopy. These procedures are becoming standard for fertility protection in cancer patients.
The advances achieved in the field of oncology in recent years have caused a dilemma. Optimized systemic oncological therapies have improved long-term survival, particularly for patients with haematological diseases. The 10-year survival rates with leukaemia and lymphoma, for example, are now approaching 90%. These successes, however, have been achieved at the cost of reduced fertility owing to premature ovarian insufficiency, resulting from the gonadotoxic side-effects of chemotherapy and radiotherapy (
). At the same time, many women say they still want to be able to have children, despite the diagnosis of cancer. One in seven of the patients would even be willing to accept reduced oncological safety if this meant it would still be possible for them to have children later (
). Non-surgical options include suppressing ovarian function using gonadotrophin-releasing hormone analogues before the start of treatment and hormonal stimulation of the ovary using FSH, with a puncture technique subsequently used to obtain oocytes, which can then be preserved in either a fertilized or unfertilized state (
For the past 10 years, the surgical procedures used, and the long-practiced repositioning of the ovaries away from the irradiation field (transposition), have also included the removal of ovarian tissue before the start of oncological treatment and transplantation of the tissue back into the patient after treatment, usually with a laparoscopic procedure in both cases. Between removal and transplantation, the tissue is preserved in a frozen state in cryobanks (
). The ovarian tissue can be transplanted orthotopically (in the ovary or the immediate vicinity, such as in the pelvic wall) or, rarely, heterotopic (outside of the ovary, such as the abdominal wall) (
Worldwide, 86 children have been born to date after transplantation of previously removed ovarian tissue, and several pregnancies are currently still in progress (
86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children.
FertiPROTEKT network Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
reported the first birth after transplantation of cryopreserved ovarian tissue in Germany (2012).
The aim of the present study was to describe the surgical and fertility-medicine complications and results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. Additional aims were to determine whether a standard surgical technique is used for removing and transplanting ovarian tissue for fertility protection, and whether the surgical complications occurring during fertility-preserving interventions differ from those associated with laparoscopy for other medical indications.
Materials and methods
The FertiProtekt network was founded in 2006 with the aim of optimizing fertility protection in patients with cancer, and has been involved in protecting women's fertility in cases of cancer for more than 10 years (www.fertiprotekt.de) (
The network now includes around 100 university and non-university centres in Germany, Austria and Switzerland. Fifteen hospitals in the network carried out transplantations up to September 2015 (Figure 1). Between May 2007 and June 2016, 1302 patients with newly diagnosed cancer in the FertiProtekt network had ovarian tissue removed for fertility preservation. The overall cohort included 85 patients with benign disease (equivalent to 6.5%). During the same period, 71 transplantations of previously removed ovarian tissue were carried out for patients wanting to have children after cancer. The 71 transplantations were carried out in 58 women. Ten women had two transplantations and three women had a third transplantation procedure. The results were obtained using a questionnaire survey that was sent to all the centres that had transplanted ovarian tissue (
FertiPROTEKT network Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
). All the centres that carry out transplantations were contacted by letter in November 2015. For the data analysis, the centres that had returned the questionnaire by June 30, 2016, and had carried out at least five removals of ovarian tissue or at least three ovarian tissue transplantations were selected. Thirteen of the 15 FertiProtekt centres returned the questionnaire by the deadline.
Figure 1FertiProtekt centres participating in this study in which ovarian tissue was transplanted up to September 2015, with numbers of procedures shown.
In this group, a retrospective analysis based on the following criteria was carried out: the surgical techniques used for removal and transplantation of ovarian tissue; the frequency of surgical complications during removal and transplantation; start of a menstrual cycle; serum oestradiol level measured at least 6 months after transplantation; and rates of pregnancies and births after transplantation. With surgical complications, a distinction was made between intraoperative complications, e.g., organ injury, and postoperative complications, e.g., postoperative bleeding. The surgical complications identified have been reported previously (
According to German law, Institutional Review Board approval was not required for this study as it reports retrospective data collected from anonymized patient data (
Konsenspapier zwischen dem Arbeitskreis Wissenschaft der Konferenz der Datenschutzbeauftragten des Bundes und der Länder und der Deutschen Arbeitsgemeinschaft für Epidemiologie (DAE).
The most frequent diagnosis in the 1302 women in whom ovarian tissue was removed for fertility protection in oncological diseases was breast carcinoma (552 women [42.4%]). Eighty-five women (6.5%) had benign diseases, e.g., premature ovarian insufficiency; Turner syndrome; and Lupus erythematosus. Details of the diagnosis were unavailable in 89 cases (6.8%) (Table 1).
Table 1Diagnoses in 1302 patients whose ovarian tissue was cryopreserved for fertility protection.
Laparoscopy was the standard method of obtaining access to ovarian tissue for removal (in 1292 women [99.2%]). Laparotomy was only carried out in 10 cases (0.8%).
Amount of ovarian tissue removed
Tissue was removed from one ovary in 97.8% of the patients (1273 out of 1302 women), and removed bilaterally in 29 women (2.2%). An incision was made in the ovary during tissue removal in two-thirds of patients (875 out of 1302 [67.2%]). The most frequently used method is to remove greater than one-third to up to two-thirds of the ovary (569 out of 1302 patients [43.7%]). One-third or less of the ovary was removed in 450 out of 1302 patients (34.6%). Ovarian biopsies less than 2 mm were taken in 247 of the 1302 women (18.9%). One whole ovary was extracted in 36 women (2.8%).
Instruments used
In most cases, scissors and scalpel were used during tissue removal, with no coagulation of the removed tissue (1044 out of 1302 women [80.2%]). Coagulation was required in 402 out of the 1302 cancer patients (30.9%), but, in only 258 (19.8%) patients, the removed tissue was affected by heat A monopolar needle in 22 out of 1302 patients (1.7%), and biopsy forceps in one patient.
Treatment of the surface of the ovary
In most patients (1001 out of 1302 [76.9%]), no reconstruction of the ovary was carried out after tissue removal. The ovary was reconstructed with sutures in 87 out of 1302 patients (6.7%). No details were given on the treatment of the surface of the ovary in 214 out of 1302 patients (16.4%).
Simultaneous surgical procedures
Unilateral salpingectomy was carried out in four patients during the laparoscopic procedure, and bilateral salpingectomy in two patients. Diagnostic hysteroscopy was carried out in 31 out of 1302 patients (2.4%) during the same procedure. One simultaneous myoma enucleation was carried out, although myomas were detected intraoperatively in 30 women (2.3%). Chromopertubation was carried out in 48 women (3.7%) during the ovarian tissue removal procedure.
Perioperative morbidity
Endometriosis was detected intraoperatively and histologically confirmed in 264 out of 1302 women (20.3%). Adhesions were present in 336 out of 1302 (25.8%), and congenital malformations around the internal genitalia in three patients (0.2%). A total of 254 out of 1302 women (19.5%) had previously undergone abdominal surgery, and five women (0.4%) had previously received radiotherapy.
Drainage tube placement
A drainage tube was placed after ovarian tissue removal in 440 out of 1302 women (33.8%).
Complications
Three complications of surgery occurred during the removal of ovarian tissue for fertility protection and before the start of oncological treatment within the FertiProtekt network. They consisted of two postoperative complications: one abdominal wall haematoma requiring revision, and one postoperative urinary tract infection (three out of 1302 [0.2%]).
Ovarian tissue transplantation
A total of 71 transplantations were carried out in 58 women (10 women had two transplantations and three women had three transplantation).
FertiPROTEKT network Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
reported the diagnoses of patients who underwent ovarian tissue transplantation after cancer treatment in the FertiProtekt network: Hodgkins lymphoma (32.7%), breast cancer (30.6%) and other malignancies (32.7%). The diagnoses for the 38 patients who received transplants in Erlangen are presented here as examples. The most frequent diagnosis was also Hodgkin's disease (15 women [39.5%]) (Table 2). The average time for storage of the ovarian tissue was 3 years.
Table 2Tumour entities in the 38 women whose ovarian tissue was transplanted after treatment for oncological diseases at Erlangen University Hospital.
The standard access route for ovarian tissue transplantation procedures in the FertiProtekt network was laparoscopy. This was selected as the primary surgical access route in 69 out of 71 transplantations (97.2%).
Transplantation site
The standard method used in 61 transplantations (85.9%) involved transplanting the ovarian tissue into a peritoneal pouch. Transplantation into one peritoneal pouch was carried out in 60 transplantations (84.5%) and into two peritoneal pouches in one case (1.4%). During transplantation into a peritoneal pouch, the peritoneum was incised without coagulation. After transplantation of the ovarian tissue, the peritoneum was closed with single sutures in 40 out of 61 transplantations (65.6%). Spontaneous adaptation occurred in 19 out of 61 transplantations, and closure was dispensed with tissue glue in two cases (3.3%). Transplantation into the ovary was carried out in 18 out of 71 transplantations (25.4%), bilaterally in two of these cases. In the process, an incision was made into the ovary in three out of 71 transplantations (4.2%); the surface of the ovary was reconstructed with sutures in seven out of 71 transplantations (9.9%); and the transplanted tissue was attached with interrupted sutures in six out of 71 transplantations (8.5%). Heterologous ovarian tissue transplantation into the subcutaneous adipose tissue of the lower arm was carried out in one patient. A preliminary laparoscopy for preparing the grafting side was not carried out in any of the transplantations.
Amount of tissue transplanted
In most cases, one-third or less of the removed ovary was transplanted (45 transplantations [63.4%]). Over one-third to up to two-thirds of the ovarian tissue was replaced in six transplantations (8.5%), and transplantation of tissue biopsies less than 2 mm in size was carried out in seven patients (9.9%). In 13 cases, no information was provided on the amount of tissue that was transplanted.
Instruments used
Most of the procedures were carried out with scissors or scalpel, without coagulation (52/71 [73.2%]). Bipolar coagulation was used in six transplantations in all (8.5%), but only minimally in two of these operations.
Simultaneous surgical procedures
In five patients (7%), diagnostic hysteroscopy was carried out during the procedure for returning the ovarian tissue. In one patient (1.4%), a surgical hysteroscopy was carried out, with excision of a polyp in the body of the uterus. Removal of a myoma or septum was not required in any of the procedures. The patency of the fallopian ducts was tested in 40 patients (56.3%), with sodium chloride in 26 cases, with methylene blue in nine, and no details were available in five cases.
Perioperative morbidity
Adhesions were found during the exploration of the abdomen in 30 transplantations (42.3%), endometriosis in 16 (22.5%) and 14 patients (23.7%) had histories, including earlier abdominal surgery (apart from the removal of the ovarian tissue). Ten of the patients (14.1%) had previously undergone radiotherapy.
Drainage tube placement
Drainage tubes had been placed after ovarian tissue transplantation in 34 transplantations (47.9%).
Hormonal stimulation
Hormonal stimulation was given in five (8%) women during ovarian tissue transplantation procedures. Supporting methods, e.g., gonadotrophin-releasing hormone agonists before transplantation, LH, FSH, or both, before transplantation, or proangiogenic substance were not given.
Histology of the transplant
Explicit histological examination of the ovarian tissue before transplantation was requested in 36 transplantations (50.7%).
The surgical techniques used to transplant ovarian tissue in the FertiProtekt network and related data from published research are presented in Table 3 and Table 4.
Table 3Techniques used in the FertiProtekt centres for ovarian tissue removal for fertility protection in cancer patients, based on the list given in
Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
a Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
Table 4Data on technical aspects of ovarian tissue transplantation for fertility protection in cancer patients in the FertiProtekt network, based on the list given in
Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
Cases, n
Surgical access route for ovarian tissue transplantation
a Key to centre numbers: 1, Bern; 2, Bonn; 3, Bremen; 4, Düsseldorf; 5, Erlangen; 6, Freiburg; 7, Heidelberg; 8, Innsbruck; 9 Mannheim; 10, Neuss; 11, St Gallen; 12, Tübingen. The dashes denotes that none of the FertiProtekt network did application of tissue adhesive to the excision surface.
In the 71 transplantations carried out in the FertiProtekt network, only one intraoperative complication occurred. Because of extensive adhesions, a switch had to be made from laparoscopy to laparotomy in one patient. This represents a complication rate of 1.4% with ovarian tissue transplantation.
Forty-seven of the 58 (81%) women wanting to have children after cytostatic therapy developed regular menstrual cycles after the ovarian transplantation. In five women, the follow-up period was too short, i.e., over 6 months, for any conclusions about the menstrual cycle to be drawn. In 36 out of 57 transplantations (63.2%), an increase in the oestradiol level to over 100 pmol/l was observed at least 6 months after transplantation, although no data were available for 15 transplantations as the follow-up period was still too short. At the time of data assessment, 16 pregnancies and nine births in 14 different women had taken place among the patients who underwent transplantation (22.5%); birth rate was 12.7% per transplantation, despite the short follow-up period (Table 5). Spontaneous conceptions occurred in 13 cases. In the other cases, IVF with intracytoplasmic sperm injection was used to achieve pregnancy.
Table 5Effect of ovarian transplantation in the FertiProtekt centres as reflected in postoperative menstrual cycles, pregnancies and births.
Criterion
n
Comments
Ovarian transplantations, n
71
Women, n
58
Transplantations with oestradiol >100 pmol/l at least 6 months after transplantation (at least once), n (%)
36 (50.7)
No data in 15 transplantations (21.1%) as follow-up too short (<6 months)
Women with menstrual cycle after transplantation, n (%)
The present data, based on 71 ovarian transplantations carried out in Germany, Austria, and Switzerland, agree with published data and show that transplanting cryopreserved ovarian tissue is a beneficial procedure with a low level of surgical risk (
). Reported pregnancy rates in the 455 patients described in published research is 14.5% to date. Within the network, 24.1% of the 58 women treated have so far become pregnant. Reasons for the rather low pregnancy rates might be difficulties in creating a favourable ovarian environment with adequate blood perfusion during the transplantation procedure, as well as the relatively older ages of the patients; it could also be attributed to the short follow-up period so far for some of the cases. A further increase in the pregnancy rate can therefore be expected in the coming months and years.
Insufficient data were available on the surgical techniques used for removing and transplanting ovarian tissue; consequently, no real standard has been set here. At most, 50% of studies included information on technical surgical criteria.
published a review of the literature on surgical techniques used to date on the removal and transplantation of ovarian tissue for purposes of fertility protection in cancer patients. The authors also discuss the problem that surgical techniques are not described in sufficient detail. Several surgical techniques have been described in multiple studies, and, in several cases, this has not been clearly detailed (
). The fertility-protection procedures evaluated here by the FertiProtekt network are intended to provide robust data to serve as a foundation for evidence-based treatment decision-making. The surgical techniques used by the network can be regarded as a guide to the surgical approach and can be used by other oncofertility centres as a procedural algorithm. The surgical standard that has emerged consists of laparoscopic removal of one-third or less to two-thirds of one ovary with scissors and scalpel without coagulation, and later laparoscopic transplantation into one (usually ipsilateral) or two peritoneal pouches, with no bipolar coagulation if possible. A learning curve was also evident within the network. Whereas more generous coagulation and suturing was carried out initially, these are now only carried out in cases of absolute necessity; for example, in cases of uncontrollable haemorrhage so that as little functional ovarian tissue is damaged as possible and to prevent adhesions and scar formation.
Several investigators have also provided no details of surgical complications encountered with the various techniques. Despite this, it is still the case that complications occurring directly because of the surgical procedures are rare. Rates of less than 1% have been reported (
). The known rate of intraoperative and postoperative major complications for operative gynaecological laparoscopy is less than 1%, and the mortality rate is between four and eight deaths per 100,000 cases (
reported a rate of 0.57% for bowel injuries and severe complications during laparoscopy procedures. Reported rates of removal of ovarian tissue and later transplantation are comparable, at 1% or 0.27%, or even lower, with a 0.1% rate of severe complications after ovarian tissue removal in our group of patients. Among the women in whom ovarian tissue was transplanted within the network, no complications associated with the surgical technique occurred. Therefore, the risks and complications of laparoscopic removal and transplantation of ovarian tissue is similar to those of standard laparoscopy.
A potential later risk for women is the possibility of tumour cells being transmitted during the transplantation procedure. Estimated risk has been reported to be around 1%. It is thought to be highest with haematological malignancies, particularly leukaemia (
). As far as we know, no cases of recurrent disease resulting from tumour cell transference during transplantation have yet been reported, and no cases have been seen among our own patients.
In conclusion, against the background of the low complication rate, increasing numbers of pregnancies and births, and increasing expertise available in centres, it can be stated that laparoscopic removal and transplantation of ovarian tissue has now become a standard procedure that should be offered to patients for fertility protection in cases of cancer.
References
Anderson R.A.
Wallace W.H.B.
Baird D.T.
Ovarian cryopreservation for fertility preservation: indications and outcomes.
Konsenspapier zwischen dem Arbeitskreis Wissenschaft der Konferenz der Datenschutzbeauftragten des Bundes und der Länder und der Deutschen Arbeitsgemeinschaft für Epidemiologie (DAE).
86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children.
Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
Matthias W. Beckmann studied Medicine at the Université Catholique de Louvain in Brussels, and the Albert-Ludwigs-University in Freiburg. In 1995, he obtained his habilitation (Adjunct Professor) at the University of Düsseldorf. He has been Director of the OB/GYN at the Friedrich-Alexander-University in Erlangen, Germany since 2001. He has also been Head of the Comprehensive Cancer Center of the European Metrolpol Region Nuremberg since 2010. His research interests are the genetic predisposition of breast, ovarian and endometrial cancer, and minimal invasive surgery.
Key message
This study provides the first analysis of the complications of surgery in the removal and transplantation of ovarian tissue. Complications were found to be rare, which is an important factor when using this fertility-preservation technique. The removal and subsequent transplantation of ovarian tissue is now becoming an established method.
Article info
Publication history
Published online: November 08, 2017
Accepted:
October 19,
2017
Received in revised form:
October 13,
2017
Received:
April 14,
2017
Declaration: The authors report no financial or commercial conflicts of interest.
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