Abstract
The topic of fertility preservation has been gaining increasing importance since the beginning of this century. The reasons for this development are the advances in oncological therapy over the past few decades, with cure rates of approximately over 90%, and the fact that starting families is increasingly postponed in later periods of life in industrialized countries. Since March 2020 the whole medical and non-medical world experiences a pandemic due to Covid-19 (coronavirus disease 2019) which has never been seen before. This created a plenty of challenges for both, the patients and healthcare providers.
This review article presents the fertility-protective methods currently available for women and men suffering from cancer with their clinical approach, value, advantages and disadvantages. Besides, it focuses on the changes and special considerations which have to be taken into account during pandemic times including preventive measures as well as the patient’s access to the fertility preserving options. In conclusion every premenopausal woman and every man with incomplete family planning suffering from cancer should be counselled about the existing fertility preserving techniques before commencing cancer therapy.
Keywords: female fertility preservation, male fertility preservation, fertility preserving methods, Covid-19 pandemic, oncofertility
INTRODUCTION
Fertility protection is a relatively new field within reproductive medicine and has to be considered in the context of fertility-impairing therapies. Fertility protection management of various cancers has improved dramatically in the past decades and the prognosis for long-term survival is getting better for many cancer diseases. As a result, the demand for fertility preservation is increasing in all our practices. Besides, family planning is increasingly postponed into later phases of life due to many personal, non-cancer related reasons. These developments lead to a raising demand for fertility preserving techniques. In general, there are medicinal and operative methods to preserve fertility in women and men, which are presented in the following.
This mini-review article is intended to provide an up-to-date overview of the currently available therapeutic options for cancer patients who wish to have children in the future. Furthermore, it reflects the changes and challenges for both, medical professionals working in the field of oncofertility as well as patients with newly diagnosed cancer and a planned gonadotoxic therapy, caused by the Covid-19 (coronavirus disease 2019) pandemic.
General considerations concerning the Covid-19 pandemic
The Covid-19 pandemic has led to a worldwide health emergency that has impacted 188 countries at last count. The rapid community transmission and relatively high mortality rates with Covid-19 in modern times are relatively unique features of this flu pandemic and have resulted in an unparalleled global health crisis. The current pandemic situation has focused the attention of healthcare service providers across the globe away from all other non-emergency health problems, including fertility. Nevertheless, fertility preservation in cancer patients has to be regarded as an urgent issue with a short window of opportunity. Where resources allow, with extra caution and strict adherence to the Covid-19 safety protocols and local guidelines, oncofertility is a feasible option, giving hope for young patients with cancer (1-4).
Newly diagnosed cancer and a future desire to have children - why is it a problem?
The topic of fertility preservation in cancer patients has been coming into the focus of medical considerations in recent years and decades. The most important reasons can be seen in the advances in the field of oncology (in hemato-oncology for example, cure rates over 90% are now achieved in certain diagnoses), but also in socio-demographic changes (5). In 2018, the average age of women in Germany giving birth to their first child rose to over 30 years for the first time (6). In other European countries a similar development can be observed. As a result, there are more and more people with incomplete family planning suffering from cancer who still want to have children later.
Although the long-term survival of oncological diseases has improved in the recent past, oncological therapies have hardly lost any of their gonadotoxicity leading to the occurrence of premature ovarian insufficiency in women or variable restrictions in sperm quality up to azoospermia in men. These oncological long-term consequences are an important reason for an unfulfilled desire to have children later in life. Alkylating agents such as cyclophosphamide, which are, for example, used in the treatment of lymphomas (R-CHOP protocol) or in the cytostatic therapy of breast cancer (EC / FAC scheme) and whole-body irradiation, e.g. before a planned bone marrow stem cell transplant, are the agents possessing the highest degree of gonadotoxicity (7). Furthermore, it has to be considered that these substances are not only utilized for the treatment of haematological neoplasms, but also for benign hematological diseases or severe autoimmune diseases. Breast cancer and lymphoma are the malignancies most frequently diagnosed in premenopausal women. It is precisely with these tumour entities that therapeutic agents are used that are particularly damaging the ovarian reserve or testicular capacity (8).
Therefore, a specialized field dealing with the topic of maintaining fertility (fertility preservation) has been established in reproductive medicine. Over the past few years, several conservative and operative methods have been established with the aim of keeping the option of starting a family in later life to young people suffering from cancer (9). The fertility preserving methods currently available are briefly described below.
Since the majority of people suffering from cancer would like to have children in the future, the recommendation for fertility-preservation measures has become a standard part of the counselling received by patients after the diagnosis of any malignancy with a consecutively planned potentially gonadotoxic therapy (10). This consultation should take place at a reproductive medicine facility specialized in fertility preservation. In 2006, the FertiPROTEKT network, meanwhile including cooperating 144 centres in Germany, Austria and Switzerland, was founded to improve patient information about fertility preservation measures. The network published a book in 2016 as a guide for practice, whose second edition as an English version was published in July 2020 (11). Surveys with affected patients found that the topic of fertility is of great importance for young women and men, and showed that one in seven patients would be willing to accept a loss of oncological safety if this would guarantee their ability to have children in later life (12).
With regard to the assumption of costs for fertility protective measures by health insurance, the situation in the various European countries is extremely heterogeneous. In some countries, such as Denmark, the costs of fertility preserving techniques are covered, while in others, such as Austria, they are not absorbed. Last year the German parliament decided that the retrieval, freezing and storage of female or male germ cells or germ tissue must be covered by the statutory health insurance. It is to be hoped that the other European countries, which are currently not yet bearing the costs of fertility preservation, will also follow this strategy.
Changes and challenges for oncofertility due to the Covid-19 pandemic
The Covid-19 pandemic caused by the Severe Acute Respiratory Syndrome (SARS) Coronavirus 2 (CoV-2) first described in China on the 30th December 2019 hit the entire globe within a few weeks (13). Lots of countries did experience a burden of their health care systems whose extent was not imaginable before. At the pandemic summit in March and April 2020, there were not enough ventilation places on the intensive care unit in many clinics and the state governments decided on a variety of measures to combat the pandemic, including curfews (14). After a decline of new infections in the summer, there has now been a sharp rise in Covid-19 diseases in almost all European countries since October 2020.
Which changes did occur in the everyday clinical practice at oncofertility centres in pandemic times?
Since oncofertility centres, like other medical facilities, were classified as systemically relevant, the state allowed their continued operation even during the pandemic. Comprehensive preventive and hygienic measures had to be implemented in order to guarantee treatment according to medical standards with the best possible safety for staff and patients. These measures were first developed in the countries being most affected by the pandemic, like Italy, and then adopted by the other countries (15). The following preventive and hygienic measures still apply to all oncofertility centres today:
1. telephone inquiries about cold symptoms and questions concerning a stay in risk areas and contact with infected people within 14 days in advance of the presentation, if necessary testing with a nasopharyngeal swab
2. obligation for all employees and visitors to wear a mask covering mouth and nose
3. refraining from handshakes when greeting and saying goodbye
4. maintaining a minimum distance of 1.5 m from other people, if possible
5. following a cough and sneeze label with sneezing into the crook of your elbow
6. installation of disinfectant dispensers at all entrances of the centre (hand disinfection after each contact with an exposure time of at least 30 seconds)
7. regularly hand washing with soap for at least 20 seconds
8. attaching plexiglass panels to the centre entrance
9. channelling the flow of patients in order to avoid large gatherings of people in the ambulance entrance or waiting room
10. avoidance of accompanying persons, unless they are absolutely necessary for the treatment
11. stay of the patients and their partners in single rooms after the oocyte retrieval, if possible
12. refusal to visit the centre by external persons (e.g. pharmaceutical representatives, inspection by authorities)
13. formation of two practice teams working independently from each other
14. limiting the number of people being present at team meetings
15. allocation of break times for staff so that no more than two people are in the lounge at the same time
16. sending prescriptions or sick leaves by post or electronically
17. extension of telephone and video consultation hours
18. regular intermittent ventilation of the centre rooms or guarantee of a controlled supply and exhaust air of each room through a modern ventilation system
Table 1 summarizes the hygienic measures to be observed by the individual groups of people.
Table 1.
Overview of the corona prevention measures that are carried out by the centre staff, the patients and accompanying persons
| Staff | Patients | Accompanying persons |
| mouth and nose protection | mouth and nose protection | mouth and nose protection |
| no handshake | no handshake | no handshake |
| minimum distance | minimum distance | minimum distance |
| hand disinfection and hand washing | hand disinfection and hand washing | hand disinfection and hand washing |
| cough and sneeze label | cough and sneeze label | cough and sneeze label |
| inquiring about cold symptoms and risk contacts | refrain from accompanying persons, if not absolutely necessary for treatment | refrain from visiting the centre, if possible |
| plexiglass panels at the centre entrance | ||
| channeling of the patient flow | ||
| expansion of telephone and video consultations | ||
| sending of prescriptions and certificates per post or via e-mail | ||
| formation of independent practice teams | ||
| no visits by external persons | ||
| planning the break times | ||
| adequate ventilation of the centre |
Hygienic measures for the IVF laboratory
Several authors suggest that during pandemic times it is highly possible that the general precautions taken during oocyte recovery or gamete/embryo manipulation will be changed during IVF treatment with virus-positive asymptomatic patients. They explain that a separate area in the laboratory will be needed. The use of physical barriers, such as glass windows, could be implemented in screening areas or around registration desks in fertility clinics, as well as in embryology laboratories, to prevent spaces and staff being exposed to the Covid-19 virus. Additionally, it is considered that the already in-use areas of the clinics (oocyte recovery rooms, sperm recovery rooms, etc.) should be cleaned and disinfected with specific products after every case. All staff should be trained in specific protocols for dealing with individuals with SARS-CoV-2, and should wear specific filtering face masks. Where a physical presence is not necessary, the use of telemedicine for any fertility inquiries, including embryological results, could minimize the spread of the virus. Finally, the authors conclude that the usual work uniform would be better replaced by one similar or even identical to the uniform for working with SARS-CoV-2 infection, for instance protective coverall shoes, and isolation clothing in a combination with a head cover (16, 17).
Which are the challenges in the treatment of oncofertility patients in Covid-19 times?
During the Covid-19 pandemic, the general goal is to pool all of the medical expertise for the care of corona intensive care patients. Elective procedures should be postponed whenever possible. The application of fertility-preserving methods is not an elective intervention, as it cannot be postponed. Nevertheless, in some regions particularly affected by the pandemic, such as Lombardy in Italy, it was temporarily not possible to adequately care for oncofertility patients (15).
It has to be considered that cancer patients are a particularly vulnerable group requiring special protection with regard to infectious diseases due to the immunosuppression occurring as an adverse effect of chemotherapy. This also applies to patients who receive immunosuppressive gonadotoxic therapies for benign diseases.
Another challenge can be seen in the fact that, especially at the beginning of the pandemic, it was not clear whether the germ cells or germ tissue of people suffering from the coronavirus were infectious. It is now assumed that no virus transmission via follicle or seminal fluid as well as germ cell tissue is possible (18). However, long term effects of Covid-19 disease on male fertility, including possible trans-generational consequences, are still unknown. Current studies are limited by the small sample size and short follow-up time. Clinical data concerning the presence of SARS CoV-2 in semen samples are still controversial. Despite several limitations of their study, Li et al. have reported the presence of SARS CoV-2 virus in the semen samples collected from six patients with Covid-19, including two recovering individuals. The findings of this study re-open the discussion on possible viral shedding in semen (19). On the other hand, Pan et al. conducted a study with 34 Chinese men recovering from a coronavirus infection finding no evidence for the detection of the novel coronavirus in semen samples (20).
Newly diagnosed cancer and a future desire to have children - how to preserve fertility under special consideration of the challenges caused by the Covid-19 pandemic?
The most important basic principle should first and foremost be a moderate application of operative and cytostatic therapies. For example, in early stages of cervical cancer, it may be possible to preserve the uterus when performing a trachelectomy which is possible up to FIGO (Fédération Internationale de Gynécologie et d`Obstétrique) stage IB. Modifications of the chemotherapeutic agents as well as adjusting the dose and duration of therapy can also reduce gonadotoxic effects. However, the effectiveness of the oncological therapy must not be jeopardized, since the most important goal is to cure the patient.
The fertility preserving techniques currently available for women and men are briefly presented below also considering their application and availability during pandemic times:
How can you help women who have cancer and who want to have children in the future?
1. Transposition of the ovaries
The ovaries are surgically relocated from the radiation field on one or both sides. This procedure can be combined with a staging laparoscopy (21). The most common indication is irradiation of the small pelvis, e.g. in patients with cervical cancer.
At the peak of the pandemic in spring 2020, some oncofertility patients had restricted access to ovarian transposition as a result of the overloading of the clinics.
2. Medical ovarian suppression with a gonadotrophin releasing hormone agonist (GnRHa)
A depot injection of GnRHa is carried out every 28 or 84 days throughout the entire period of chemotherapy (beginning shortly before the initiation of chemotherapy, and ending approximately two weeks after completion of chemotherapy). It is supposed that this will result in a downregulation of the ovary with consecutively reduced intake of cytostatics. The main side effect are climacteric complaints. If the therapy lasts more than 6 months, a so-called add back therapy with an estrogen and a progestin is recommended to counteract the serious consequences of sex hormone deficiency such as osteoporosis (22). As the administration of GnRHa alone is not very effective as gonadal protection during chemotherapy, it is not recommended as the sole fertility preserving method (23).
There are no restrictions for this fertility-preserving method due to the Covid-19 pandemic.
3. Oocyte cryopreservation
Hormonal stimulation with gonadotrophins is followed by oocyte retrieval and cryopreservation of unfertilized oocytes. Gonadotrophin stimulation can be started in any phase of the cycle (24). This reduces the time delay until the start of oncological therapy. The time span required for harvesting oocytes is now only about two weeks, so that oocytes can be removed in almost all types of malignancies, apart from acute hematological neoplasms like acute leukemia or lymphoma with severe mediastinal involvement. However, this procedure is not an option for prepubertal girls. About a third of women who use this method will become pregnant (25).
There are no relevant restrictions for this fertility-preserving method due to the Covid-19 pandemic.
4. Embryo cryopreservation
Instead of unfertilized oocytes, fertilized ova (e.g. in the pronucleus stage or later in the embryonic development) can also be cryopreserved and stored if there is a stable partnership. The advantage of this procedure is the higher survival rate of the cryopreserved embryo, which is at least twice as high as unfertilized oocytes, especially after application of vitrification technique (26). The disadvantage of freezing embryos is that the patient is tied to a specific partner. In addition, many young women do not yet have a steady partner with whom they plan to start a family in the future.
There are no relevant restrictions for this fertility-preserving method due to the Covid-19 pandemic.
5. Cryopreservation of ovarian tissue
This approach involves laparoscopic removal of ovarian tissue with subsequent cryopreservation before the start of cytostatic therapy followed by laparoscopic transplantation of the thawed tissue after oncological therapy and a relapse-free or metastasis-free interval (Fig. 1). This procedure can also be offered to prepubertal girls (27). Ovarian tissue cryopreservation allows both, the possibility of maintaining reproductive and endocrine organ function. In some cases, activation of the contralateral ovary can also be observed after transplantation of ovarian tissue. The pregnancy rate using this procedure is around 30% and will further increase (28). However, reluctance to transplant ovarian tissue is advisable in the case of malignant hematological diseases (especially leukemia) and ovarian tumours due to the potential risk of ovarian metastasis. Maturation of follicles in vitro (in vitro maturation) could be an option in such cases (29).
Figure 1.
Laparoscopic transplantation of thawed ovarian tissue into a peritoneal pocket after completed oncological therapy.
At the peak of the pandemic in spring 2020, some oncofertility patients had restricted access to operative laparoscopy for ovarian tissue transplantation as a result of the overloading of the clinics. These procedures often have been postponed by the clinics as there is no emergency indication.
How can you help men suffering from cancer who would like to have children in the future?
1. Sperm cryopreservation
Cryopreservation of sperm is usually obtained after masturbation, however, if ejaculation is not possible, sperm can be obtained through electrical or vibrator stimulation with the use of anaesthesia (30). This procedure cannot be offered to prepubescent boys (31).
There are no restrictions for this fertility-preserving method due to the Covid-19 pandemic.
2. Cryopreservation of testicular tissue
Cryopreservation of testicular tissue is an experimental approach, which is still not available for boys and men with malignancies to preserve their fertility. Until today, it has just been performed in animals. Several tissue samples are taken from both testes and are cryopreserved. In the future they might be used for fertilization ex-vivo (32). However, it is important to note that there are no existing methods at this time for restoring fertility using this tissue. Nevertheless, there might be treatment options utilizing this tissue in the future. This method is the only available fertility preserving method for prepubescent boys.
Table 2 summarizes the fertility preserving methods available for women and men with advantages and disadvantages. Table 3 summarizes the fertility preservation options in women and men for reader`s digest.
Table 2.
Advantages and disadvantages of the different fertility preserving methods available for women and men
| Method | Advantages | Disadvantages |
| Ovarian transposition | low operative complication rate, can be combined with staging laparoscopy | surgical risks, no protection against systemic cytostatic side effects |
| Medical ovarian suppression with GnRHa | non-invasive | limited effectiveness, climacteric side effects, initially agonistic effect on the GnRH receptor (flare-up) |
| Cryopreservation of oocytes | no abdominal surgery required, possibility of creating a fertility reserve | start of therapy is delayed by approximately 2 weeks, not an option for prepubertal girls, potential risk of side effects with hormonal stimulation / puncture |
| Cryopreservation of embryos | no abdominal surgery required, possibility of creating a fertility reserve, higher survival rate after thawing | start of therapy is delayed by approximately 2 weeks, not an option for prepubertal girls, potential risk of side effects with hormonal stimulation / puncture, need for a partner |
| Cryopreservation of ovarian tissue | preservation of reproductive and endocrine ovarian function, the only option for prepubertal girls, practically no delay in oncological therapy (only 1-2 days) | necessity of 2 surgical interventions (usually laparoscopy), possibility of transplantation of tumour cells |
| Cryopreservation of sperms | non-invasive, no delay of therapy | not an option for prepubertal boys, often restricted ejaculate parameters for adolescents |
| Cryopreservation of testicular tissue | creation of a large fertility reserve | Still experimental (it is currently not possible to restore fertility with this tissue), invasive approach |
Table 3.
Summary of the existing fertility preservation options in women and men
| Fertility preservation options in women | Fertility preservation options in men |
| transposition of the ovaries | cryopreservation of sperms |
| GnRHa for ovarian suppression | cryopreservation of testicular tissue |
| cryopreservation of oocytes | |
| cryopreservation of embryos | |
| cryopreservation of ovarian tissue |
Newly diagnosed cancer and a future desire to have children - what should you know?
Every patient with newly diagnosed cancer and who may wish to have children in the future should be informed about her or his fertility preservation options by a doctor specialized in reproductive endocrinology. If the person suffering from cancer wishes to carry out fertility-preserving measures, a close interdisciplinary cooperation between reproductive medicine and oncology and, if necessary, other specialist areas is in the best interest of the patient. The international professional associations American Society for Reproductive Medicine (ASRM Covid-19 Task Force) and The Society for Assisted Reproduction Technology have also issued special recommendations on fertility preservation, adapted to the current pandemic situation. Their guidelines emphasize that fertility preserving measures have to be regarded as an emergency treatment that should be carried out without delay, taking into account the compulsory hygiene measures (33).
The current Covid-19 pandemic is a challenge for both reproductive endocrinologists and patients requesting fertility preservation. Due to the increasing importance of fertility protection measures, it is important to provide the techniques preserving and restoring fertility even in pandemic times. A normalization of clinical practice can only be expected when an effective coronavirus vaccine is available.
Conflict of interest
The authors declare that they have no conflict of interest.
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