Interventional procedure overview of removal, preservation and reimplantation of ovarian tissue to restore fertility after gonadotoxic treatment
Closed for comments This consultation ended on at Request commenting lead permission
Evidence summary
Population and studies description
This interventional procedures overview is based on about 550 transplantation procedures from 3 systematic reviews, 1 retrospective cohort study, 1 multicentre case series and 1 registry analysis. Some patients had more than 1 OTT and there is patient overlap between the studies. This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 6 studies as the key evidence in table 2 and table 3, and lists 78 other relevant studies in table 5.
The systematic review by Ni Dhonnabhain et al. (2022) included 39 studies on patients with cancer, 24 of which reported outcomes for ovarian tissue cryopreservation. Studies on embryo cryopreservation and oocyte cryopreservation were also included. According to the Newcastle-Ottawa scale, 21 studies were of good quality, 10 were fair and 8 were poor (6 of which were on ovarian tissue cryopreservation). Of the 24 studies on ovarian tissue cryopreservation, only 6 were described as prospective.
The systematic review by Gellert et al. (2018) reported outcomes from 360 procedures in 318 women published in peer-reviewed papers in combination with data from a Danish cohort. Evidence came from 21 countries, including Europe, North America, South America, Asia and Australasia. The mean age at OTC was 28.9 years and the mean age at first transplant was 33.5 years. Among the diagnosis, breast cancer and haematological malignancies, were the main reasons for fertility preservation but non-malignant conditions were also included.
The systematic review by Khattak et al. (2022) included 87 studies with 735 women, 568 of whom were included in the meta-analysis. All studies that reported fertility or endocrine outcomes from either fresh or frozen–thawed ovarian transplants were included. Evidence came from many countries including Europe, North America, South America, Asia and Australasia. Of the 319 women for whom age at OTC was reported, 283 (89%) were 35 years or younger. Most of the included studies were small and there was clinical heterogeneity in the studies used for the meta-analysis. Authors of the included papers were contacted for individual patient data if relevant outcomes were not reported in the published manuscripts.
A retrospective cohort study of 1,302 women who had OTC, 58 of whom had OTT was reported by Beckmann et al. (2018). The data came from the FertiPROTEKT network, which covers Germany, Austria and Switzerland. The aim of the study was to evaluate complications associated with the removal and transplantation of ovarian tissue. Questionnaires were analysed from 13 centres that had done at least 5 removals of ovarian tissue or at least 3 ovarian tissue transplantations. The review by Dolmans et al. (2021) of 285 women who had OTT also included data from the FertiPROTEKT group, together with data from Denmark, Spain, Belgium and France. Case series with more than 20 women having OTT were included. The mean age at OTC was 29.3 years and the mean age at first OTT was 34.6 years. More recent results from the FertiPROTEKT network were reported by Lotz et al. (2022). This retrospective registry analysis included 196 women who had OTT with at least 12 month follow up. The mean age at OTC was 31.3 years and the mean age at OTT was 35.9 years.
Table 2 presents study details.
Study no. | First author, date country | Patients | Age | Study design | Inclusion criteria | Intervention | Follow up |
|---|---|---|---|---|---|---|---|
1 | Ni Dhonnabhain B, 2022 Country not reported for individual studies | Patients attempting pregnancy using cryopreserved cells or tissues frozen before cancer therapy. 550 ovarian tissue transplants (number of patients not reported), 102 embryo transfers (n=75), and 178 oocyte transfers (n=170) | Not reported | Systematic review and meta-analysis (39 studies) | Women at risk for infertility because of gonadotoxic medical treatment; completion of oocyte, embryo, or ovarian tissue cryopreservation procedures; documented follow-up, including reproductive or obstetric outcome; and articles with original data. Ovarian tissue transplants done exclusively for endocrine purposes, where there was no desire to conceive, were excluded. Cases using in vitro matured oocytes and fertility preservation because of gender reassignment therapy or surgery were also excluded. Case reports, conference abstracts, and review papers were excluded. | Oocyte, embryo, or ovarian tissue cryopreservation. Some women had more than 1 ovarian tissue transplantation, when there was no return of menses or when menses ceased after some time. | Not reported |
2 | Gellert S, 2018 Authors of review were based in Denmark. Procedures were done in 21 countries, including Europe, North America, South America, Asia and Australasia. | n=318 women who had OTT (360 procedures) | Mean age at OTC was 28.9 years (range 9 to 47 years). Mean age at first transplant was 33.5 years (range 13 to 47 years). | Systematic review and Danish cohort study (n=89 women, 115 procedures) | All peer-reviewed publications mentioning OTC and OTT in humans were included. Cases involving fresh OTC were excluded. In addition, data from pregnancies and live births from oocyte donations, patients in whom the date of conception was estimated to coincide with the date of transplantation, and patients in whom premature ovarian insufficiency had been diagnosed at the time of OTC were excluded. Data from patients who had had OTT before December 2017 in the Danish cohort were also included. | Transplantation of frozen thawed ovarian tissue. Ovarian tissue was grafted orthotopically (n=233), heterotopically (n=23), or both (n=17). The transplantation site was unknown for 87 procedures. Of the 306 procedures, 318 were first transplantations, 39 were second and 3 were third transplantations. | Not reported |
3 | Khattak H, 2022 Procedures were done in many countries, including Europe, North America, South America, Asia and Australasia. | n=735 (87 studies); 568 women were included in the meta-analysis. Women who received ovarian transplants, including frozen–thawed transplant, fresh or donor graft. | Age was reported for 319 women. Of these, 283 had their ovarian tissue retrieved at age 35 years or younger. | Systematic review | All studies that reported fertility or endocrine outcomes from either fresh or frozen–thawed ovarian transplants for at least 1 patient were included. These comprised cohort studies, observational studies, case reports, case series, conference abstracts and grey literature (irrespective of country of origin, affiliations of authors, language or year of publication). Studies that reported 5 or more cases of ovarian transplants were included in the statistical analysis. | Frozen-thawed, fresh or donor graft ovarian transplants. There were 45 fresh transplants, 11 of which used a graft from a donor (twin sister). In 237 women for whom it was reported, 225 (95%) had laparoscopy and 12 (5%) had laparotomy for ovarian tissue collection. For transplantation, surgical approach was reported for 323 women; 205 (64%) had laparoscopy and 95 (29%) had laparotomy. The site of transplant varied and included orthotopic (a remaining ovary) and heterotopic sites (such as pelvic side wall or peritoneal pocket). | Not reported. |
4 | Beckmann M, 2018 Germany, Austria, Switzerland (FertiPROTEKT network group) | n=1,302 women who had OTC. 58 women had a total of 71 transplantations | Not reported | Retrospective cohort study | 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 30 June 2016 and had done at least 5 removals of ovarian tissue or at least 3 ovarian tissue transplantations were selected. Of the 15 FertiProtekt centres, 13 returned the questionnaire by the deadline. | Ovarian tissue was removed by laparoscopy in 1,292 (99%) women. A drainage tube was placed after ovarian tissue removal in 34% of women (440 of 1,302). In most cases, one-third or less of the removed ovary was transplanted. | Not reported |
5 | Dolmans M, 2021 Denmark, Spain, Belgium, France and the FertiPROTEKT network group from Germany, Switzerland, and Austria. | n=285 women who had OTT | Mean age was 29.3 years (range 9 to 44) at OTC and 34.6 years at first OTT. | Review (multicentre case series) | Case series with more than 20 women having transplantation reported by European clinical centres or groups were included. | 277 (97.5%) women had orthotopic OTT, 3 had both orthotopic and heterotopic transplantation, and 5 had only heterotopic (subcutaneous abdominal wall or forearm) transplantation. 59 patients had a second OTT and 7 patients a third. | Not reported. |
6 | Lotz L, 2022 Germany, Austria and Switzerland (FertiPROTEKT network) | n=196 women who had OTT | Mean 31.3 years (range 17 to 44) at OTC and 35.9 years (range 23 to 47) at OTT. | Registry analysis (retrospective) | Women who had OTC and OTT after malignant (n=191) or non-malignant diseases (n=5). Transplantations were done between 2007 to 2019, with follow up till December 2020. | Orthotopic OTT. 43 patients had repeated transplantations; 39 had a second transplantation and 4 had a third transplantation. Collection, transportation and freezing of tissue were done according to the recommendations provided and published by the network FertiPROTEKT. | At least 12 months after OTT. |
Efficacy outcomes | Safety outcomes | |
|---|---|---|
Ni Dhonnabhain, 2022 | Clinical pregnancy rate (cumulative number of clinical pregnancies per transfer for oocytes and embryos and per transplant for ovarian tissue)
A random effects analysis found no statistically significant differences among subgroups (p=0.09). Live birth rate (cumulative number of live births per transfer for oocytes and embryos and per transplant for ovarian tissue)
A random effects analysis found no statistically significant difference among the 3 subgroups (p=0.11). Miscarriage rate (cumulative number of miscarriages per transfer for oocytes and embryos and per transplant for ovarian tissue)
A fixed effects analysis found a statistically significant difference (p=0.02) among subgroups. Further fixed analyses showed no difference in miscarriage rates between the oocyte and embryo subgroups and significantly fewer miscarriages with ovarian tissue cryopreservation compared with embryo cryopreservation (p=0.01). No analysis was done comparing ovarian tissue with oocytes, as the effect size was the same. | No safety outcomes were reported. |
The mean time from cryopreservation to first transplantation was 4.4 years (range 0.3 to 13.9 years) Endocrine function At the first OTT, endocrine function was restored for 95% (225 of 237) of cases (45 had unknown status). Mean period from OTT to follicular function=4 months (range 1 to 8, n=83) Of the 39 patients who had a second OTT and 3 who had a third transplantation, endocrine function was reported in 29 and the status was unknown for the remaining 10. The mean period from the second OTT and third OTT to follicular function was 3.9 months (range 2 to 6, n=13) and 4.5 months (range 3 to 6, n=2), respectively. Pregnancies and live births Of the 318 patients, 170 wished to restore fertility (data was unavailable for 123). In total, there were 131 pregnancies in 95 patients, counting both biochemical and clinical pregnancies. This resulted in 87 live births in 69 women, and a total of 93 children born. There were 81 singleton pregnancies, 6 twin pregnancies and 10 pregnancies ongoing. The age of patients who succeeded in having a live birth or ongoing pregnancy were significantly younger at OTC (mean 26.4 years, range 9 to 38 years) than patients who failed to conceive but had a pregnancy wish (mean 29.6 years, range 14 to 39 years); p=0.0019 Method of conception 46% of pregnancies and 51% of live births were conceived spontaneously. Perinatal outcomes From the 40 children in whom data were available, birth weight and gestational age were similar to children born from normal pregnancies. | Recurrence of malignancy Of the 264 patients for whom the diagnosis was known, 230 (87%) had malignant disease and 34 (13%) had benign disease. From the cohort of 230 patients with malignancy, 9 had a recurrence after OTT, 4 of whom died. None of the recurrences were considered to be directly caused by the OTT. Perinatal outcomes From the total 93 children born, 1 was reported with a chromosome anomaly. A patient with a family history of limb malformations had a child with fetal arthrogryposis. | |
Khattak, 2022 | Pregnancy rate (18 studies, n=547)
184 women had at least 1 pregnancy and the overall total number of pregnancies reported in the literature was 290. Pregnancy rates were higher when ovarian tissue was cryopreserved at age 35 or younger (OR 0.35, 95% CI 0.13 to 0.92; p=0.03, I2=0%). Of the pregnancies for which mode of conception was known, 199 (69%) were conceived naturally. Live birth rate (17 studies, n=539)
134 women had at least 1 live birth and the total number of live births of women included in the meta-analysis was 166. In addition to the 17 studies included in the meta-analysis, there were 34 live births described in case reports. Overall, 189 live births have been reported in the literature. Miscarriage rate (15 studies)
The mean age at cryopreservation in women who had miscarriages was 27.8 years. Endocrine function Oestrogen (8 studies), pooled means (pmol/litre)
An increase in oestrogen of >200 pmol/litre was noted in 117 women (75%) after transplant. The median time to return of oestrogen to a value >200 pmol/litre was 19.5 weeks (IQR 14 to 24 weeks, range 5 to 208 weeks). FSH (11 studies, I2=79%), pooled means (IU/litre)
A decrease in FSH below 25 IU/litre was achieved in 72% (135/187 women). The median time to return of FSH to a value <25 IU/litre was 19 weeks (IQR 15–26 weeks, range 0.4 to 208 weeks). Luteinizing Hormone (6 studies, I2=0%), pooled means (IU/litre)
A decrease below 15 IU/litre was achieved in 67% (46/69) of women. The median time to return to a value <15 IU/litre was 19.5 weeks (IQR 14 to 27 weeks, range 8 to 156 weeks). Return of menstruation
Duration of graft function (19 studies, n=181)
| Risks of surgery The included studies did not report any specific complications related to ovarian transplantation other than those of gynaecological laparotomy and laparoscopic surgery. Complications included skin infection and injury to surrounding organs. Risk of subsequent cancers in the ovarian graft There were 2 case reports of cancer in the transplanted ovarian graft. One report diagnosed the recurrence of granulosa cell tumour in a patient at caesarean section delivery. The patient had not received any adjuvant chemotherapy beforeoophorectomy for ovarian tissue cryopreservation. In another case, a patient who was treated for Ewing's sarcoma and had ovarian tissue cryopreserved before receiving chemotherapy, presented with an ovarian mucinous cystadenoma in the transplant. |
Beckmann, 2018 | Return of menstruation 81% (47/58) of women wanting to have children after cytostatic therapy developed regular menstrual cycles after the ovarian transplantation. In 5 women, the follow up period was too short for any conclusions about the menstrual cycle to be drawn. Oestradiol level An increase in the oestradiol level to over 100 pmol/litre was seen after 63.2% (36/57) transplantations after at least 6 months. No data were available for 15 transplantations as the follow up period was still too short (less than 6 months). Pregnancy and birth rate At the time of data assessment, 16 pregnancies and 9 births in 14 different women had taken place among the patients who had transplantation (22.5%); birth rate was 12.7% per transplantation. There were 3 miscarriages and 4 ongoing pregnancies. Method of conception Spontaneous conceptions occurred in 13 cases. In the other cases, IVF with intracytoplasmic sperm injection was used to achieve pregnancy. | Complications Postoperative complications after removal of ovarian tissue=0.2% (2/1,302):
Complications associated with ovarian tissue transplantation procedure=1.4% (1/71)
Transference of malignant cells No cases of recurrent disease resulting from tumour cell transference during transplantation were identified. |
Dolmans, 2021 | Pregnancy rate Of the 276 women wishing to conceive, pregnancy rate was 38.4% (106/276). Women who became pregnant were statistically significantly younger at OTC than those who did not become pregnant (mean age 26.9 versus 29.8 years, p=0.005). Reimplanted tissue is still functioning in many women in the current study, and more pregnancies are likely to follow. Live birth rate
Miscarriage rates
Number of children
IVF outcomes Of the 109 women who had IVF, only 54 (50%) had an embryo transfer; 39 (36%) women conceived and 23 (21%) gave birth. The empty follicle rate was available for 53 women, yielding a 31% rate of follicles without an oocyte. Resumption of menstruation Of 258 patients who had OTT and had available follow up data, 204 had a diagnosis of premature ovarian insufficiency, of whom 181 (88.7%, ranging from 77.6% to 97.2 % according to centre) had resumption of endocrine function, as shown by resumption of menstruation. The mean interval between transplantation and first menstruation was 4.5 months. Graft survival In a subgroup of 45 women with more than 5 year follow up, the 5-year graft survival rate was 55% with a correlation between the duration of ovarian function and age at the time of OTC, regardless of whether chemotherapy was previously administered. OTT after pelvic irradiation Of the 285 women, 36 (12.6%) had some kind of pelvic irradiation before OTT. In this group, there were 9 pregnancies and 7 live births (19%), with differences depending on the disease. There were no live births in the 15 women with anal or cervical cancer who needed a high radiation dose. Effect of chemotherapy before OTC Data on chemotherapy was available for 95% (271/285) of women, 50 (18.5%) of whom were exposed to chemotherapy before OTC. The rate of resumption of ovarian function was not significantly different in those who had chemotherapy before OTC compared to those who had not (90% versus 85.3%, p=0.49). The rates of pregnancy in women who were previously exposed to chemotherapy were 50.0% compared with 28.1% in those who had not had chemotherapy before OTC (p=0.004). Univariate and multivariate analyses of pregnancy outcomes suggested that exposure to chemotherapy before OTC does not alter the results of OTT. | Recurrence of malignancy
The time from transplantation to relapse ranged from 2 months to 10 years. All relapses were dependent on the primary disease and not related to OTT. All were distant from the grafting site, and most were very close to the location of the primary cancer. The cohort included 2 patients with acute myeloid leukaemia, neither of whom had a relapse after OTT. In both cases, the ovarian tissue was frozen after chemotherapy. |
Lotz, 2022 | Pregnancy rate per patient=32.7% (95% CI 26.1 to 39.7%) There were a total of 80 pregnancies from 244 transplantations. Patients who became pregnant after the first transplantation were younger at the date of cryopreservation (mean 29.9 years) compared to those without a pregnancy (mean 31.9 years, p=0.01). Both patient groups also differed regarding age at the time of transplantation (with pregnancy: mean 34.8 years versus without pregnancy mean 36.4 years; p=0.02). In women younger than 35 years at the time of OTC, pregnancy rate after first transplantation was 34.5% (95% CI 26.7 to 42.9%) versus 20.4% (95% CI 10.6 to 33.5%) in women who were 35 years or older. Live birth rate per patient=26.5% (95% CI 20.5 to 33.3%) In women younger than 35 years at the time of OTC, live birth rate after first transplantation was 28.2% (95% CI 20.9 to 36.3%) versus 16.7% (95% CI 7.9 to 29.3%) in women 35 years or older. Method of conception
Repeated transplantations
Outcomes by centre In centres with 10 or more transplantations (n=5 centres), the pregnancy rate was 34.1% (46/135) after first transplantation. In centres with fewer than 10 transplantations (n=21 centres), the pregnancy rate was 22.9% (14/61) after first transplantation (p=0.12). No difference in pregnancy rates was observed after pelvic irradiation. However, only 17 (8.7%) women had a history of pelvic irradiation and pregnancy occurred in only 3 of them. | No safety outcomes were reported. |
Procedure technique
Most of the transplantations were orthotopic but a small proportion were heterotopic, and some were both. Most of the studies only included transplantation of frozen–thawed ovarian tissue but the systematic review by Khattak et al. (2022) also included a small number of fresh or donor grafts. In this review, laparoscopy was the most common approach for both collection (95%) and transplantation (64%) of ovarian tissue. Some women had a second or third OTT.
Efficacy
Pregnancy rate
All 6 studies reported the pregnancy rate. In the systematic review by Ni Dhonnabhain et al. (2022), the clinical pregnancy rate (defined as the cumulative number of clinical pregnancies per transfer for oocytes and embryos and per transplant for ovarian tissue) was 44% for ovarian tissue cryopreservation (22 studies, I2=67%), 35% for oocyte cryopreservation (7 studies, I2=24%) and 49% for embryo cryopreservation (9 studies, I2=0%). In the systematic review by Gellert et al. (2018), 170 of the 318 women were known to have a desire to restore fertility. There were 131 pregnancies (biochemical and clinical) in 95 women. In the systematic review by Khattak et al. (2022), the pregnancy rate was 37% (95% CI 32 to 43%) for frozen transplants and 52% (95% CI 28 to 96%) for fresh transplants. Of the 547 women included in 18 studies, 184 had at least 1 pregnancy and the total number of pregnancies reported was 290. Pregnancy rates were higher when ovarian tissue was cryopreserved at age 35 or younger (OR 0.35, 95% CI 0.13 to 0.92; p=0.03, I2=0%).
In the cohort study of 1,302 women who had OTC, 58 women had a total of 71 transplantations and there were 16 pregnancies (23%) in 14 women (Beckmann 2018). In the case series of 285 women who had OTT, pregnancy rate was 38% (106/276) in those wishing to conceive. Women who became pregnant were statistically significantly younger at OTC than those who did not become pregnant (mean age 26.9 versus 29.8 years, p=0.005; Dolmans 2021). In the registry study of 196 women who had OTT, pregnancy rate per patient was 33% (95% CI 26 to 40%). There were a total of 80 pregnancies from 244 transplantations. Patients who became pregnant after the first transplantation were younger at the date of cryopreservation (mean 29.9 years) compared to those without a pregnancy (mean 31.9 years, p=0.01). Both patient groups also differed regarding age at the time of transplantation (with pregnancy: mean 34.8 years versus without pregnancy mean 36.4 years; p=0.02; Lotz 2022).
Live birth rate
All 6 studies reported the live birth rate. In the systematic review by Ni Dhonnabhain et al. (2022), the live birth rate (defined as the cumulative number of live births per transfer for oocytes and embryos and per transplant for ovarian tissue) was 32% for ovarian tissue cryopreservation (20 studies, I2=82%), 26% for oocyte cryopreservation (8 studies, I2=8%) and 35% for embryo cryopreservation (9 studies, I2=17%). In the systematic review by Gellert et al. (2018), 170 of the 318 women were known to have a desire to restore fertility. There were 87 live births in 69 women. The age of patients who succeeded in having a live birth or ongoing pregnancy were significantly younger at OTC (mean 26.4 years, range 9 to 38 years) than patients who failed to conceive but had a pregnancy wish (mean 29.6 years, range 14 to 39 years; p=0.0019).
In the systematic review by Khattak et al. (2022), the live birth rate was 28% (95% CI 24 to 34%) for frozen transplants and 45% (95% CI 23 to 86%) for fresh transplants. Of the 539 women included in 17 studies, 134 had at least 1 live birth and the total number of live births reported was 166. In addition to the 17 studies included in the meta-analysis, there were 34 live births described in case reports.
In the cohort study of 1,302 women who had OTC, 58 women had a total of 71 transplantations and the birth rate was 13% per transplantation (Beckmann 2018). In the case series of 285 women who had OTT, the live birth rate was 26% (75/285); Dolmans 2021). In the registry study of 196 women who had OTT, the live birth rate per patient was 27% (95% CI 21 to 33%). In women younger than 35 years at the time of OTC, live birth rate after first transplantation was 28% (95% CI 21 to 36%) versus 17% (95% CI 8 to 29%) in women 35 years or older (Lotz 2022).
Miscarriage rate
Miscarriage rate was reported in 4 of the 6 studies. In the systematic review by Ni Dhonnabhain et al. (2022), the miscarriage rate (defined as the cumulative number of miscarriages per transfer for oocytes and embryos and per transplant for ovarian tissue) was 8% for ovarian tissue cryopreservation (13 studies, I2=29%), 9% for oocyte cryopreservation (5 studies, I2=27%) and 17% for embryo cryopreservation (6 studies, I2=0%).
In the systematic review by Khattak et al. (2022), the miscarriage rate from 15 studies was 37% (95% CI 30 to 46%) for frozen transplants and 33% (95% CI 13 to 89%) for fresh transplants. The mean age at cryopreservation in women who had miscarriages was 27.8 years.
In the cohort study of 1,302 women who had OTC, 58 women had a total of 71 transplantations and there were 3 miscarriages (Beckmann 2018). In the case series of 285 women who had OTT, the miscarriage rate was 13% (38/285); Dolmans 2021).
Endocrine function
Endocrine function or return of menstruation was reported in 4 studies. In the systematic review by Gellert et al. (2018), endocrine function was restored for 95% (225/327) of women (45 had unknown status). The mean period from OTT to follicular function was 4 months (range 1 to 8, n=83).
In the systematic review by Khattak et al. (2022), an increase in oestrogen of more than 200 pmol/litre was reported in 117 women (75%) after transplant (8 studies). A decrease in FSH below 25 IU/litre was reported in 72% (135/187) women and a decrease in luteinizing hormone below 15 IU/litre was reported in 67% (46/69) of women. Return of menstruation was reported in 72% (196/273) of women after a median follow up of 18 weeks (range 3 to 48 weeks).
In the cohort study of 1,302 women who had OTC, return of menstruation was reported for 81% (47/58) of women after OTT. An increase in the oestradiol level to over 100 pmol/litre was reported after 63% (36/57) of transplantations that had at least 6 months follow up (Beckmann 2018). In the case series of 285 women who had OTT, 89% (181/204) of women who had premature ovarian insufficiency and had available follow up data resumed menstruation. The mean interval between transplantation and first menstruation was 4.5 months (Lotz 2022).
Method of conception
The method of conception was reported in 4 studies. In the systematic review by Gellert et al. (2018), 46% of pregnancies and 51% of live births were conceived spontaneously. In the systematic review by Khattak et al. (2022), 69% of pregnancies for which the mode of conception was known (n=199) were conceived naturally. In the cohort study by Beckmann et al. (2018), 81% (13/16) of pregnancies were conceived spontaneously. In the registry study of 196 women who had OTT, 62% of conceptions were spontaneous (Lotz 2022).
Duration of graft function
Duration of graft function was reported in 2 studies. In the systematic review by Khattak et al. (2022), the median duration of function was 2.5 years (range 0.7 to 5 years) reported in 15 studies. In 3 further studies, the pooled duration of function ranged from 1.2 to 7.7 years. In the case series of 285 women who had OTT, 5-year survival of the graft was 55% in a subgroup of 45 women (Dolmans 2021).
Perinatal outcomes
From the 40 children in whom data were available, birth weight and gestational age were similar to the general population (Gellert 2018).
Safety
Few safety outcomes were reported and 2 of the 6 studies did not report any safety outcomes.
Perioperative complications
The systematic review by Khattak et al. (2022) stated that there were no specific complications related to OTT other than those of gynaecological laparotomy and laparoscopy surgery. Complications included skin infection and injury to surrounding organs (not further described).
Postoperative complications after removal of ovarian tissue were reported in less than 1% (2/1,302) of women in the cohort study of 1,302 women who had OTC. There was 1 abdominal wall haematoma needing revision and 1 urinary tract infection. For the transplantation procedure, there was 1 conversion from laparoscopy to laparotomy because of extensive adhesions (Beckmann 2018).
Malignant cells in ovarian graft
In the systematic review of 87 studies by Khattak et al. (2022), there were 2 case reports of cancer in the transplanted ovarian graft. Chemotherapy had not been offered before OTC in both cases.
Recurrence of malignancy
In the systematic review by Gellert et al. (2018), 4% (9/230) of women who had malignant disease had a recurrence after OTT. None of the recurrences were considered to be directly caused by the OTT. In the case series of 285 women who had OTT, recurrence of malignancy was reported in 4% (12/285). The time from transplantation to relapse ranged from 2 months to 10 years. All relapses were dependent on the primary disease and not related to OTT. All were distant from the grafting site, and most were very close to the location of the primary cancer (Dolmans 2021).
Perinatal outcomes
From the total 93 children born, 1 was reported with a chromosome anomaly; a patient with a family history of limb malformations had a child with fetal arthrogryposis (Gellert 2018).
Anecdotal and theoretical adverse events
Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).
They listed the following theoretical or anecdotal adverse events:
Operative risks associated with laparoscopy, including bleeding, organ damage, pain, infection and port site hernia
Theoretical risk of reimplanting malignant cells within the ovarian tissue
Earlier menopause
The intervention may be unnecessary if the treatment is not gonadotoxic
Delay to start of treatment (but this is much less of a problem with tissue storage than with embryo or oocyte storage)
Nine professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.
Validity and generalisability
There are data from Europe, North America, South America, Asia and Australasia. The systematic review by Gellert et al. (2018) includes 2 case reports from the UK.
Only a small proportion of women who have had ovarian tissue removed and cryopreserved have had the tissue reimplanted. It is possible that, because the procedure can be offered before puberty, many patients are not yet at a family-planning stage of their life.
The systematic review by Ni Dhonnabhain et al. (2022) excluded procedures that were done only for endocrine purposes, with no desire to conceive.
Most of the women had been diagnosed with cancer but some women with benign conditions have also been reported.
Outcomes of the procedure may differ according to the type of cancer and treatments such as pelvic radiation may also impact pregnancy outcomes.
Surgical techniques differ across centres, regarding the removal of ovarian tissue, the site for reimplantation and the amount of tissue that is reimplanted. Most of the transplantations were orthotopic but a small proportion were heterotopic.
In the systematic review by Khattak et al. (2022), it was noted that most centres used slow freezing as a method of ovarian tissue cryopreservation with only 13 cases reported using vitrification.
Some women had chemotherapy before the ovarian tissue was removed and others had it removed after chemotherapy. There is some limited evidence to suggest this may not affect the outcomes.
Some women may have residual hormonal function from a remaining ovary.
Duration of graft function was only reported in 2 studies.
One author of the systematic review by Ni Dhonnabhain et al. (2022) was Co-Founder and Chief Operations Officer of Hertility Health Ltd. Three of the authors of the systematic review by Khattak et al. (2022) were shareholders in Profam, a private company that offers ovarian tissue cryopreservation and transplantation services. All other authors in the 6 studies declared no conflict of interest.
Ongoing trials
Development of Ovarian Tissue Autograft in Order to Restore Ovarian Function (DATOR) (NCT02846064); single group assignment; n=50; France; study completion date October 2022
Cryopreservation of Ovarian Tissue for Potential In Vitro Maturation or Autologous Transplantation (NCT01558544); single group assignment; n=100; US; study completion date December 2023
Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome (NCT03381300); single group assignment; n=106; the Netherlands; study completion date November 2071
Gonadal Tissue Freezing for Fertility Preservation in Individuals at Risk for Ovarian Dysfunction and Premature Ovarian Insufficiency (NCT04948658); prospective cohort study; n=100; US; study completion date July 2030
Biorepository in Participants Who Undergo OTC for Gonadotoxic Therapy (NCT05440617); prospective case series; n=100; US; study completion date September 2041
How are you taking part in this consultation?
You will not be able to change how you comment later.
You must be signed in to answer questions