Author: Eleni Pap.

Emergency fertility preservation for medical reasons

Emergency fertility preservation (EFP), a new field in Medically Assisted Reproduction, provides assistance to patients who face the risk of losing their fertility when there is an urgent need to start treatments, such as chemotherapy, radiation, other medical treatments, or surgery. Fertility preservation methods offer the opportunity to these patients, to possibly have a child, at a later time, after they have been successfully treated.

Over the past decades, survival rates among young cancer patients have steadily increased. Advances in the field of oncology, especially in early detection and treatment management, improved the prognosis of cancer patients. As a result, quality of life after treatment became an important consideration for these patients in recent years.

According to National Statistics, the average age of first time mothers in developed countries continues to rise, making it likely that more women will be nulliparous at the time of diagnosis of cancer. This fact adds a greater focus to the need for fertility preservation in those women.

International guidelines state that timely information and consultation on methods and options for EFP should be provided to all patients of young age when planning gonadotoxic treatments, before they start their treatment.

In most cancers, the treatment strategies used, such as chemotherapy, radiotherapy or ovaries surgery, may lead to reduction or loss of ovarian function with consequent subfertility and premature ovarian insufficiency. Novel targeted therapies, increasingly used by oncologists, have a largely unknown impact on reproductive function. The degree of damage to ovarian function depends on the type and dose of chemotherapy and radiotherapy, the woman’s age as well as the initial ovarian reserve of the woman. Therefore, EFP consultation should be thorough, evidence-based and individualized.

Women should be advised that cryopreservation of embryos and oocytes are methods clinically established for female fertility preservation. Ovarian tissue cryopreservation is considered to be an innovative method, offered where oocyte/embryo cryopreservation is not feasible or at patient preference. In vitro maturation of oocytes (IVM) is regarded, at present, as an innovative FP procedure, performed when oocyte cryopreservation is required but ovarian stimulation is not feasible. Cumulative live birth rates are dependent on the age of the woman at the time of EFP and indication for cryopreservation.

For embryo or/and oocyte cryopreservation (in case of a single woman or a woman who does not wish to preserve embryos), hormonal stimulation with gonadotropins is needed, to induce multiple follicle recruitment aiming at obtaining more than one mature oocyte per treatment cycle.

As there is often an urgent need to start cancer treatment, new protocols to facilitate the start of the ovarian stimulation have been proposed, using a GnRH antagonist. GnRH antagonist protocols minimize the time required for ovarian stimulation and can also be applied with random initiation (random start), that is, regardless of the woman’s cycle day. Consequently, ovarian stimulation can start immediately, with no significant delay to the start of the cancer treatment. In general, the time to egg retrieval is shortened to about 2 weeks in most cases.

Anti-estrogens, such as letrozole, are co-administered alongside gonadotropins, in an effort to reduce potential harm associated with high estradiol levels and increase the safety of stimulation protocols for women with breast cancer undergoing EFP.

Ovarian tissue cryopreservation requires a surgical procedure, in which the ovary is entirely or partially removed, processed, frozen, and stored for future use. The advantage of ovarian tissue cryopreservation is that it does not require ovarian stimulation with medication and can be performed immediately. When the patient wishes to become pregnant and a multidisciplinary medical assessment is completed, the ovarian tissue is then thawed and re-implanted. Resumption of normal ovulatory menstrual cycles has been reported in over 90% of patients within a 4–9 months’ period after transplantation.

At a time when urgent treatment for serious medical reasons is needed, decision-making regarding fertility preservation is stressful.  It is of outmost importance to allow for high-quality decision-making by providing information and a thorough and individualized fertility consultation to these patients.

Women’s emotional adjustment to IVF

In vitro fertilisation (IVF) is a method of treating infertility, which is time-consuming and invasive, and requires a medication regime that lasts many days, as well as anaesthesia; besides, it has a high rate of failure to achieve pregnancy. All this generates stress and anxiety and has a negative impact on the quality of life of the couple.

Firstly, it should be noted that individuals who end up undergoing IVF treatment have been facing long-standing infertility problems and have undergone a variety of tests and, possibly, treatment regimens for extended periods of time. The difficulty in achieving pregnancy is a particularly stressful factor and a mentally painful affair, which couples have difficulty dealing with. Chronic infertility presents high rates of mental exhaustion, as a result of intense stress and anxiety. Feelings of guilt, shame, fear, anger, and pessimism may lead to depression, they may negatively impact sexual desire, and may lead to social isolation.

Couples with infertility issues have both their own anxiety regarding how the problem will be managed, and they are called upon to deal with a wide range of other concerns, reactions, and pressure from their families and their broader social circle with the negative consequences this creates.

The truly stressful process of IVF is added to this already psychosocially burdened environment the couple has been facing due to chronic infertility. Stress and anxiety levels in these individuals increase with the intensification and duration of the treatment (Doper et al, 2015).

Various factors contribute to the appearance or intensification of the such symptoms. Thus, older women, whose health is already suffering (hypertension, diabetes, etc.), who may be unwed, unemployed or of a low educational, social, and economic level, face a greater risk of suffering such psychological burden. Furthermore, women who have experienced the inability to complete a cycle of IVF or the failure to achieve pregnancy are affected more intensively.

Quality of life, according to the World Health Organisation, is defined as a broad concept impacted in a complicated manner by physical health, mental state, personal beliefs, levels of independence of the individuals involved, and their relationship to their environment and its conditions (social, economic, cultural, safety, etc.). Thus, all the problems related to the physical and mental health of the couple negatively impact their quality of life.

A question that was first posed years ago was whether psychological pressure and its consequences negatively impact fertility or the progress and development of IVF.

While infertility and IVF clearly impact mental health in a significant number of people to some extent, there is no assurance that the opposite is true. The correlation of psychological pressure and associated feelings with reduced fertility and failure of IVF is a long-standing field of scientific dispute.

However, meta-analyses in related research have concluded that stress has no significant statistical impact on IVF outcome (J.Boivin et al 2011, Lin Kong 2019), while, on the contrary, achieving spontaneous conception or pregnancy after IVF significantly reduces any mental burden in most infertile couples.

All research seems to come to the same conclusion. Regardless of the negative or positive impact stress levels have on infertility and IVF treatment, one of the primary goals of health professionals tackling this matter should be the provision of valid information and advice, along with psychological support. Infertility and its treatment are problems for the couple, not for an individual, and they should be treated as such.

There are many ways and many tools to measure the psychological burdens and the quality of life in correlation to infertility and the IVF process, as well as several potential treatments for them. Interventions to reduce and relieve the various clinical symptoms (stress, anxiety, fear, depression, etc.), regardless of whether or not these increase pregnancy rates (Consinean et al 2007, Domar et al 2015, Lin Kong 2019), may be exceptionally beneficial for the emotional balance and harmonious relationship of the couple.

Embryo transfer: fresh or frozen cycle?

Currently available data suggests that freezing all embryos and transferring them in subsequent cycles increases the chances of getting pregnant and reduces the likelihood of complications during pregnancy and childbirth.

Aristotle University of Thessaloniki, Scientific Partner, FIVI Medically Assisted Reproduction Unit, Inter-Balkan Medical Centre, Thessaloniki

According to the pregnancy rates published every year by the European Society of Human Reproduction and Embryology, the average success rate for embryo transfer right after egg retrieval, in a fresh cycle, is around 29%, both for traditional in-vitro fertilization and for microinsemination.

If a couple has excess embryos following a fresh embryo transfer, the surplus embryos are frozen to be thawed and transferred in a subsequent cycle. This increases their odds of conceiving by 8%.

Consequently, on the basis of the above, a quick response to the dilemma ‘fresh or frozen embryo transfer’ would be that it is preferable to transfer the embryos in a fresh cycle, as pregnancy rates are higher.

However, this approach does not take into account the fact that embryos transferred in the frozen cycle are those that were not selected for transfer in the fresh cycle and, thus, of a lower quality, which means they are less likely to lead to pregnancy.

More importantly, we need to know whether the endometrium that will receive the valuable embryos is affected by ovarian stimulation. If this is the case, it would be better to consider the all-freeze strategy, i.e. freeze all embryos and transfer them in a later cycle.

In this subsequent cycle, the endometrium will not have suffered the consequences of our effort to allow more follicles to develop, in order to create several eggs and embryos and be able to select the best in quality for the transfer.

Does ovarian stimulation have an impact on endometrial quality?

It is now clear that ovarian stimulation is linked to an abnormal endometrial development at both the histological and genetic level, regardless of the stimulation method.

Do the chances of pregnancy increase after embryo transfer in a frozen cycle as compared to the transfer of embryos in a fresh cycle?

Although there is only a small number of studies answering this question, the data published so far suggest that the likelihood of pregnancy is higher after frozen cycle transfer. It should be noted that the women who took part in these studies were randomized to either have their embryos immediately transferred in a fresh cycle or have them all frozen and then thawed and transferred in a later cycle.

Are the pregnancies resulting from fresh cycles different from those resulting from frozen cycles?

Pregnancy following frozen-thawed embryo transfer – as compared to pregnancy after fresh cycle transfer – is associated with:

• a smaller chance of intrauterine growth retardation
• a smaller chance of birth weight < 2500 g
• a smaller chance of premature birth < 37 weeks
• a lower rate of perinatal mortality
• a lower rate of postpartum bleeding for the mother

On the basis of the above data, it is obvious that freezing all embryos for later thawing and transfer at a subsequent cycle has significant advantages and should be discussed with the couple, especially if their previous IVF attempts were unsuccessful.