Pregnancy after malignant disease – challenges and possibilities

Introduction

The incidence of malignant disease increases with age and reaches its peak after 50 years of age. But, on the other hand, there is a significant number of children and young women in reproductive age who suffer malignancies. In the last few decades, treatment of malignant disease has improved significantly. Thus, there is a significant increase in children, adolescents and young people who reach the first 5 years, with a realistic chance of survival. Around 80% of patients in whom malignant disease is diagnosed before age 15 will survive the first 5 years, and 70% of them will survive 10 years after being diagnosed [1]. Carcinoma occurrence in children has increased in the last decades. But it is encouraging that survival rates have increased as well. In Europe, children’s cancer survival rates are higher in Northern countries and lower in Eastern ones. In Great Britain, children’s survival rate within 10 years is about 75%. This figure is more than double that of 50 years ago [2]. Unfortunately, in developing countries, this rate is still very low: 10% for a 5-year period [3]. Child malignancies are different from adult ones. The most frequent tumors affecting children are as follows: leukemia (the most frequent, accounting for 30%), brain and spinal cord tumors, Wilms tumor (nephroblastoma), neuroblastoma and lymphoma (both Hodgkin and non Hodgkin). Patients being diagnosed between 15 and 29 years of age account for 2% of all invasive cancers in the United States, which is about 700,000 new cases every year. It is also estimated that over 1,000,000 women of reproductive age have suffered cancer. In Europe, the estimated number is 130,500 annually [4], [5], [6]. Longer life expectancy is the main reason for the increased number of young women surviving cancer who are considering motherhood in the future.

With regard to future pregnancies, some questions that should be addressed when facing cancer in children, adolescents and young women are discussed in the following.

How is fertility preserved when treating malignant disease?

When a patient is facing a malignancy, the main objective is healing. But at the same time, the treatment plan should be carefully selected and should take into account the patient’s reproductive future.

Most oncologic treatments imply specific gonadotoxic effects. Chemotherapy with alkylating agents and abdomen-pelvic irradiation may produce a reduction in primordial follicles that, in turn, causes temporary or permanent ovarian function loss. This may manifest as acute ovarian insufficiency either during treatment, shortly thereafter or later as premature-early menopause, even before 40 years of age [7], [8].

The gonadotoxic effect depends on the age of the patient (her ovarian reserve [OR]), the chemotherapeutic agents used and their dosage. If the treatment plan includes pelvic irradiation, this may worsen the patient’s reproductive function in the future.

Five groups of alkylating agents are the first line of chemotherapy, although they have the most potent gonadotoxic effect, especially if they are used in combination. Some of such agents are cyclophosphamide, ifosfamide, melphalan, busulfan and chlorambucil, and these are the agents with a higher risk. Cisplatin and carboplatin, with low cumulative doses, and Adriamycin, are of intermediate risk. Treatment protocols with bleomycin, actinomycin D, vincristine, methotrexate and fluorouracil, without alkylating agents, are of low risk [9].

The gonads are very sensitive to radiotherapy, and the extent of damage that it may cause depends on the dose and irradiation field. High radiation doses on the hypothalamus and pituitary, as well as total body irradiation, can produce gonadotropin deficiency and secondary hypogonadism [10]. Whole abdominal or pelvic radiation also implies a high risk of fertility loss.

The standard treatment of ovarian and endometrial cancer has been hysterectomy and bilateral salpingo-oophorectomy. This surgery causes total fertility loss. Recently, less radical approaches are being used to preserve fertility. Thus, fertility-sparing surgical options should be considered in young women with early-stage, well-differentiated cervical, ovarian or endometrial low-grade tumors or in those with tumors with low malignant potential [11].

A study conducted in 2010 that included 14 European centers showed that although each of these centers had an average of 15 patients who fulfilled strict criteria for treatment with a less radical approach, only 10 patients out of more than 200 were treated this way. This indicates the need for specialized centers for fertility-sparing treatments of gynecological malignancies [12].

When deciding the cancer treatment plan, nowadays, it is mandatory that the patient and her parents are given a clear explanation of both the benefits, in terms of survival, as well as the associated morbidity, including the risk of a large percentage of ovarian function loss after treatment. Based on the age of the patient, her OR and comorbidities, the recommended treatment should be classified with regard to fertility. Treatment plans with 80% risk of permanent amenorrhea should be considered as high risk; those with a 40–60% risk of permanent amenorrhea, as medium risk; and those with <20% chance of permanent amenorrhea, as low risk. Also, fertility preserving strategies should be extensively discussed with the patient and/or her family.

Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are the best available markers of ovarian function both before and after treatment, as well as for subsequent monitoring [13]. Measuring serum AMH levels for evaluating OR should not be done only immediately after the end of cancer therapy, but it should also be repeated later on. Recovery of AMH levels after cancer therapy indicates restoration of the pool of small growing follicles. Unfortunately, the absence of recovery indicates important loss of the primordial follicle pool.

Post-treatment AMH levels reflect the quality of OR and provide an estimate of the woman’s fertile period (future fertility and reproductive life-span).

Onco-fertility counseling before treatment should provide answers and support in making treatment decisions. Therefore, it is important that treatment teams include oncologists as well as fertility specialists.

Great contributions in deciding the adequate cancer treatment plans for young women who have not yet fulfilled their motherhood wishes come from The American Society of Clinical Oncology, published in 2006 [14] and updated in 2013 [15], and from the European Society for Medical Oncology, which published its recommendations in 2013 [16]. Based on available scientific evidence, recommendations regarding surgical treatment of reproductive system malignancies, as well as the chemotherapy and radiotherapy regimens, are put forward. Also, recommendations on fertility preserving procedures, like embryo, oocyte or ovarian tissue cryopreservation, and ovarian protection with gonadotropin-releasing hormone agonists, are made.

As the results of oocyte vitrification techniques have improved dramatically, this alternative has become the standard of fertility preservation in young women, as pointed out by the American Society of Reproductive Medicine [17].

Several registries and prospective studies are ongoing to evaluate the feasibility, safety, and efficacy of fertility preserving strategies in cancer patients.

How and when can a patient become pregnant after cancer treatment?

There are multiple factors that may influence women’s fertility after cancer treatments. The chance of achieving a spontaneous pregnancy in patients after malignant disease is 40% lower than in the general population, and depends especially on the type of malignancy. The pregnancy occurrence in women after having had melanoma or thyroid gland cancer does not differ from that of the general population, while survivors of leukemia, cervical cancer or breast cancer have lower rates of subsequent pregnancies. These latter have a 70% lower chance of achieving a spontaneous pregnancy compared to the general population [16]. Therefore, these women frequently need to undergo assisted reproduction techniques (ARTs) to become pregnant. These women can be treated using their own oocytes or donor ones, depending on whether they have previously done an autologous oocyte or ovarian tissue preservation or not.

Luke and coworkers reported outcomes after ART among women with a history of cancer [18]. Their data show that live birth rates did not differ significantly either by cancer status (60.4% for women with any cancer vs. 64.5% for women without cancer) or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer) after ART procedures using donor oocytes in these women. In ART procedures with autologous oocytes, those women with a history of cancer were significantly less likely to become pregnant and to have a live birth than those without. Among cancer survivors, the probability of having a live birth in those who became pregnant after ART did not differ significantly from that of women without cancer.

There is no optimal time to get pregnant after cancer treatment as it depends on the type of malignancy, stage of the disease, individual risk of relapse, type of treatment, etc. But women should postpone pregnancy after finishing cancer treatment for at least 2 years, in order to confirm the remission. This period is important to enable assessment of any complication caused by the treatment. At this time, secondary effects connected to chemotherapy that may complicate pregnancy, like cardiac disease, diabetes, hepatic and renal disease, as well as the late effect of cardiotoxicity, can be ruled out.

In women having had breast cancer, the recommendation would be to postpone pregnancy until 3–6 months after finishing hormonal and/or biological therapy.

In any case, a thorough medical exam must be done before making a decision regarding pregnancy, in order to evaluate the damages that a gestation could cause to the woman with a history of oncological treatment. Following this medical assessment, a multidisciplinary team, including at least an oncologist and an obstetrician, will set the optimum time to get pregnant.

Is pregnancy safe – what is the risk of a fetus developing malignant disease after birth?

The main risks affecting the offspring of women after oncologic treatments are prematurity, low birth weight (LBW), genetic diseases and congenital anomalies. Recent follow-up studies of children, teenagers and young women surviving cancer and their offspring are very encouraging. They have not found a relationship between the use of chemotherapeutics and/or radiation and an increase in congenital diseases, genetic disorders or malignancies in the offspring. There is no proof of altered male-to-female sex ratio having an that might indicate increased germ cell mutagenicity and transmission of lethal X-linked mutations. But these women have an increased incidence of premature birth and of having an offspring with LBW, as well as neonatal distress and admission to the neonatal intensive care unit. No differences were found in the incidence of cytogenetic syndromes, as of nonhereditary cancer among the offspring of these women [19], [20], [21]. Patients who have been treated with abdominal-pelvic irradiation have an increased risk of premature delivery. This may be related to irreversible changes in the myometrium, including fibrosis and reduced vascularization. In these patients, deliveries by caesarean section are increased.

Can pregnancy cause disease progression?

Pregnancy after malignant disease remains a dilemma for patients because of the concern of relapse. Every patient should be assessed individually in order to evaluate her health status, including her overall health, the primary cancer, the treatment received and the possible side effects of the treatment. Pregnancy after breast cancer is especially challenging because of the hormonal influence on the tumor itself. The most recent prospective studies have not found an increased relapse rate during pregnancy in women with a previous history of breast cancer. Even more, pregnancy may be protective in these women: a meta-analysis of 14 retrospective studies has shown a 41% lower incidence of relapse when compared to women who did not get pregnant after treatment [22].

Who should be involved in the follow-up of pregnancy in those patients?

As these are high-risk pregnancies, they should be managed by multidisciplinary teams of physicians including oncologists, obstetricians, neonatologists, endocrinologists, cardiologists, hematologists, etc.

What are the health systems possibilities in third-world countries and what are their way of solving this very important problem?

On one hand, a large number of developing countries are still trying to reduce high maternal mortality rates, and, on the other, high proportions of cancers are detected at a very advanced disease stage in the same countries. Most of these countries still do not have national registries of malignant diseases, maternal deaths or delivery complications. It is estimated that 85% of all cancers affecting children occur in developing countries, where the survival rate is <10% for the first 5-year period [3]. Children often go untreated, and those who start treatment do not finish it in more than 50% of the cases. Also, these countries suffer high rates of pregnancies in teenagers, and pregnancy and delivery complications in an otherwise healthy population, that focus the efforts of their health systems. Considering all the above, it is necessary that developing countries take all precautionary steps in order to increase diagnostic procedures and screening, thus facilitating the detection of malignant diseases in early stages. That would help to select the best oncological treatment, which in turn would result in an increased survival of treated children and improve the quality of life of children, teenagers and young women. This would also increase the chance for pregnancy after treatment of malignant diseases. One of the alternatives that may help to solve this specific problem is the twining approach model, based on the close cooperation of pediatric oncology centers in developing countries with health systems of developed ones. There are some countries in Central and South America that have already started to use this model. It is also very important to start national registries, which would help to detect critical points and to stablish priorities with regard to the treatment of these patients.