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The knowledge about the effect of cancer during pregnancy and the effect of cancer progression in pregnancy is of crucial importance for the success of the mother’s treatment and favorable outcome for the fetus. There are contradictory reports that have been published regarding the outcomes of these patients.

In 1880, Samuel Gross stated that breast cancer during pregnancy would behave like a rapidly growing disease, including with an “excessively malignant” clinical course (12). In 1943, after treating 20 patients with breast cancer, a group at Columbia University Presbyterian Hospital concluded that pregnancy “made the disease inoperable” (13). Ten years later, it was consensual that abortion was linked to improved patient survival (12). A population-based cohort study of 15,721 women diagnosed with breast cancer, of whom 1,110 (7%) had cancer during or within 2 years after pregnancy, revealed that this subset of patients had a worse prognosis, validating previous data (14). Conversely, a multicentric registry containing 447 women with breast cancer during pregnancy and 865 non-pregnant counterparts, showed similar overall-survival in both groups, after adjusting for known prognostic factors (15). Nonetheless, a careful interpretation of these studies should be taken, given the heterogeneity of the patient populations and treatments prescribed (16).

So far, there is no consolidated expert opinion on whether pregnancy can induce the occurrence or relapse of cancer and if it correlates only with maternal or also with other external or endogenous risk factors.

During the last decades, imaging of the pregnant patient has been performed with radiography, computed tomography, magnetic resonance imaging, scintigraphy, positron emission tomography scan, and ultrasonography (US). US imaging has emerged as the primary imaging modality because it provides real-time images without the use of ionising radiation (16).

A clear link between the severity of fetus impairment, gestational stage, and cumulative radiation dose received has already been established (16). For instance, during the organogenesis, there is a higher likelihood of major induction malformations and the threshold dose is above 100 mGy. There are also other issues besides ionising radiation. The radioactive iodine (I-131) crosses the placenta and has the ability to affect fetal thyroid and gadolinium teratogenic in animal studies. More invasive imaging tests should only be performed if the diagnosis and/or staging is expected to contribute decisively to the prognosis of the mother or fetus and that the risks and benefits are perfectly clarified and understood by the mother (16, 17).

Although the fetus is unscathed by laboratory tests, our main concern will be the influence that pregnancy will have on diagnosis, staging and follow-up, due to the fact that the serum biomarkers lack sensitivity and specificity during this period. There are tumor biomarkers that may be increased, such as CA 15-3, SCC, CA 125, and AFP, and others that are not so much, such as the example of CEA, CA 19-9, LDH, AMH, and HE-4. Inhibin B and LDH increased in the last trimester may be a laboratory sign of hypertensive abnormalities linked to pregnancy (4).

The main challenge while managing cancer in pregnancy is balancing therapeutic regimen and fetus welfare. In addition, as an estimated 50% of pregnancies are unplanned, many women are exposed to teratogens before realising they are pregnant (13). This condition demands attention and careful protocols.

Approximately 0.5% of all births occur before the third trimester of pregnancy and the majority of these very early deliveries result in neonatal deaths and more than 40% in infant deaths. The delivery before 23 weeks of gestation, usually leads to neonatal death (5%–6% survival), and among rare survivors remains significant morbidity (98%–100%). When delivery is anticipated near the limit of viability, the patient, families and healthcare teams are faced with complex and ethically challenging decisions (18, 19). For most cytotoxic and targeted therapies, there is a lack of data regarding the risk of teratogenesis, based on case reports and retrospective series. The potential mutagenic, teratogenic and carcinogenic effects of ionising radiation and cytotoxic agents in the embryo are well known and depend on the dose, nature of the compound, treatment field and gestational stage. Some authors advocate that, if pregnancy occurs while the patient is under endocrine treatment (e.g., tamoxifen) or chemotherapy, a pregnancy termination should be recommended if it is done in the first trimester.

Pregnancy appears as an exceptional circumstance in medical ethics as the primary medical principle Primum non nocere can be questioned, as the access to the fetus occurs exclusively through intervention on the pregnant mother and treating the mother may imply harming the fetus. This is a unique situation since the welfare of both mother and fetus must be considered on any treatment planning.

When a conflict arises in the maternal-fetus dyad, caregivers must understand the pregnant woman´s mindset, broad social network, values, cultural, and religious beliefs, as this may impact their decisions (27). Consequently, it is imperative to promote the autonomy and physical integrity of the pregnant woman, ensuring that all available information on pregnancy and cancer outcomes is provided in order to allow for a fully informed consent consistent with her values (28) since the woman’s decision is absolute and unlimited. Therefore, in cases when the woman’s decision may harm her fetus (e.g., treatment of cancer during the first trimester) coercion to force treatment is never justified.

To date, there is no data systematically collected reporting the decision-making process of women who had cancer and pregnancy at the same time. Although, there are two studies conducted in the United Kingdom reporting patient experiences with participation in ORACLE (29) (evaluate the possibility that treatment with antibiotics prolongs labor and improves neonatal outcomes in women who are less than 37 weeks pregnant and experiencing either pre-term labor or premature rupture of membranes) and in the Magpie Trial (30) (prophylactic use of anticonvulsants for women with severe preeclampsia). In these studies, the major motivating factors were identified as self-benefit (it can help treat mother condition), benefit for your child (it can minimize the associated risks for the fetus) and altruism (participation can help future women or is it for the sake of medical science). It was also shown that, although some women seek the opinion of family and friends, they have little involvement or influence in women’s decisions. The partners played a role in providing a second opinion for many women, but study participants rejected the idea that their relatives or friends were in a position to influence their decision. In parallel, it may be reasonable to consider, in the future, the option of offering pregnant women with cancer the possibility of participating in clinical trials and/or enrolling in registries, increasing the motivation and the expectation of benefits for them and the fetus.

In the child-to-be perspective, there are extra layers of ethical complexity to address, because the antineoplastic treatment typically affects not only the pregnant woman but also the fetus. The developing fetus clearly has no capacity for autonomous choice, and there is no formula for balancing the interests and moral claims of the fetus with those of the mother. Furthermore, the welfare of the fetus is typically not independent of the interests of its mother (31).

When a conflict arises in the maternal-fetus dyad, such as cancer treatment and the risk of fetal demise, a range of ethical frameworks may be useful in the decision-making process. It is clear that the physician has beneficence-based and autonomy-based obligation to the pregnant cancer patient (32). Because of an immature central nervous system, the fetus cannot meaningfully be said to possess values and beliefs, although this is tremendously arguable.

Hence, scientifically there cannot be autonomy-based obligations to any fetus, although women’s beliefs may hasten her to judge differently (32). However, the physician can have beneficence-based obligations to the fetus, if the fetus is considered as a patient (33). The pregnant woman is free to withhold patient status, confer patient status, or, after conferring it, withdraw it from her pre-viable fetus (32). The fetus has no claim to patient status independently of the pregnant woman’s autonomy. When the woman is uncertain about or is not able to confer the status, the fetus can be provisionally regarded as a patient (32, 33). However, these approaches have been criticized for their tendency to emphasize the divergent rather than shared interests of the pregnant woman and the fetus. In fact, in most cases, the interests of the pregnant woman and fetus actually converge (28).

Whenever a pregnant woman is presented with a cancer diagnosis, several ethical concerns addressing technicalities must be approached, while keeping in mind the surrounding emotional issues.

There is no established modus operandi for the physician, which raises pertinent questions: i) should the patient be included in the decision-making to the best of her abilities in a limited way, or should paternalistic decision-making take over? ii) Should a proxy decision-maker decide based on the perceived patient’s best interest? (20) These are queries that can be carefully grasped by solving real-life cases, in parallel those that will be presented later.

To allow for an informed decision, the patient must be well aware of multiple medical facts, such as cancer prognosis, the possibilities of antineoplastic therapy, its main toxicities and its aim, namely: whether curative or palliative, if it will improve quality of life, or overall and progression-free-survival, if there is a risk of pre-term delivery or if peripartum complications are expected.

The timing of treatment must also be considered—is the mother symptomatic and needs to initiate treatment quickly or is it possible to delay it until the third trimester, when there is no significant risk for fetal defects in a short and long-term? Besides technical issues, before starting the treatment, the physician must consider emotional issues, such as the possibility of the child-to-be meeting its mother.

There are several established ethical frameworks for conflict resolution and decision-making. Pragmatic theoretical approaches include case-based analysis, the ethics of care, feminist theory, and traditional ethical principlism that scrutinizes the framework of autonomy, justice, beneficence, and non-maleficence. In addition, society and practitioner values could benefit this complex process.

For instance, the 1987 paradigmatic case of a pregnant woman in her late 20s, who had a late lung relapse 15 years after Ewing´s sarcoma diagnosis brought these issues to ahead. Although fully committed to saving her life, at the end of the second trimester, it became clear that the patient was dying. The Medical Centre tried to insist upon an early Cesarean section delivery in order to save her fetus. She refused the intervention with the support of her family, knowing it would almost certainly kill her, but the hospital forced the delivery through a court order. Both the patient and her extremely premature baby survived for only a short while after the surgery. In 1990, the Court of Appeals posthumously vacated the court-ordered Cesarean section, holding that the patient is totally autonomous to make healthcare decisions for herself and her fetus and that only in the most exceptional circumstances should a pregnant woman’s right to refuse interventions be called into question (34). Despite the media exposure of this case, others with similar ethical issues were far from being elucidated (35–37).

This first case is an example of what should not be done in ethical terms when approaching such a complex and sensitive context. It was noticeable that there was no multidisciplinary management and strategy for a balanced approach to outline cancer and pregnancy facts of the case and the non-medical issues to achieve the best ethical possible scenario (Figure 2).

It is possible to infer that the woman would be in mental conditions to take a position. Hence, all the best possible information, at that moment, namely the cancer and pregnancy outcomes for the woman, evidence-based treatment options and available supportive measures for the situation, should have been presented to the patient. Furthermore, the comparison with previous similar ethical scenarios and the consultation of guidelines should have been assessed and discussed, in a multidisciplinary gathering, comprising the whole medical specialities related to this subject (e.g., Medical Oncology, Obstetrics, among others), a representative of the ethics committee, all the stakeholders (such as the patient’s family and the fetus’ father) and the patient itself. Finally, the patient’s final decision, in collusion with the autonomy ethic’s principle, should have been respected.

In 2016, on February 20, a 17-week-pregnant woman in her late 30s, collapsed after an intracerebral haemorrhage, probably related to a late recurrence of kidney cancer diagnosed 10 years earlier (40). Soon after physicians declared her brain dead (41). The hospital ethics committee and the family were enquired. It was explained to both parties - mother’s family and the fetus’ father—that, to allow for the fetus survival, the woman should be kept on life-sustaining treatment to reach at least its 32 weeks, the earliest date doctors felt that a successful Cesarean delivery would be possible (40). This emphasizes the role of the “mother’s body as a cadaveric incubator”, “mother as the organ donor and fetus as the recipient”, and the concern for “possible damages to the fetus” (42–44). Some professionals believe that it is not ethically acceptable to maintain the mother’s body after brain dead to use it as a “fetal container.” Such a decision should not be assumed, but it must be debated. If the mother is to be considered a “cadaveric incubator” with no autonomous rights, the rights of the fetus should legally prevail. Another argument claims that the continued somatic support itself is actually organ donation with the fetus as the recipient (42–44). The family strongly expressed that the mother would have wanted her life preserved in order to give the fetus a chance for survival. The ethics committee equated the fetus life to a child at risk and allowed the support to the brain-dead mother. The decision was taken in a meeting of the neurosurgical, critical care, obstetrics, neonatal, transplant and ethical staff, along with the patient’s family. One hundred seven days later, the baby was born healthy, and the life-sustaining machines were turned off (40, 41).

About 10 years earlier, a woman of the same age and gestational stage as in the previous case suffered a stroke secondary to the brain progression of melanoma. Soon after, the doctors declared brain dead. Her family also decided to keep her alive to give the fetus a chance. It became a race between the fetus’ development and cancer that was ravaging the patient’s body. The baby was born about 2 months prematurely, and tragically did not survive. At that time, the case was also considered to be notable because there was no controversy (43).

Put into perspective, the two aforementioned cases have analogous ethical issues, however, with different endings. Nevertheless, both these situations follow the best ethical possible scenario approach (Figure 2). Since both patients were declared brain dead, none of them would be mentally suitable to take a position. Thus, the patient’s family and the fetus’ father should be responsible for the decisions regarding equally the patient and the fetus welfare. As observed, in these circumstances, all of the stakeholders had received the best information possible vis-à-vis the cancer and pregnancy outcomes, the evidence-based treatment options to follow pregnancy and supportive measures for maintenance of “cadaveric incubator”, with the aim for the survival of the fetus. All the decisions were engaged with a multidisciplinary team, taking into consideration previous comparable clinical cases, and respecting the patient’s family and fetus’ father autonomy. Since the number of cases describing the management of extended maternal somatic support after brain death is limited, every case should be continuously reassessed and adapted along with the increasing experience and knowledge (42–44).

In these difficult cases, mainly before the third trimester, the sovereign decision should be taken after thorough discussion between mother (or legal substitute) and the treating physician (42–46). While respecting the principle of autonomy, another final ethical issue is the right of the physicians to conscientiously object to certain treatment options.

As stated before, physicians should not bias with their recommendations and should present to consider three scenarios: i) treatment during pregnancy, with close monitoring for side effects and reconsideration of termination before viability; ii) treatment with termination of the pregnancy; and iii) treatment delay until fetal lung maturity, when it’s reasonably safe to deliver the baby (34, 47).

All over Europe, there are differences between countries regarding availability, conditions and gestational limit. In Portugal, since 2007, and after a National Referendum, the voluntary termination of pregnancy until 10 weeks of gestation was legalized (law n°16/2007). In that same legal document, it is stated that in case of danger of death or physical and/or psychic injury, the possibility of interrupting the pregnancy until 12 weeks of gestation is allowed (48).

The available international guidelines recommend that maternal fetal medicine consultation should include counseling on maintaining or terminating a pregnancy, including a review of the treatment options. These guidelines support a framework of shared decision-making in the context of maternal-fetal conflict to provide guidance for compassionate conflict resolution. An ethics consultation may be helpful to mediate conflict resolution. Intervention by the courts is rarely appropriate or indicated and should be avoided (27, 47, 49).

Based on a validated method for analysing and working up clinical ethical problems, we suggest an adaptation of an algorithm for biomedical decision-making in pregnancy-associated cancer (Figure 2).

The first task in this ethical decision-making process is to establish the medical and pregnancy facts of the case. The second step is to determine pertinent non-medical issues, which is more challenging. These steps are followed by an assessment of the goods relevant in the case. The immediate concern is clearly what is suitable for the woman medically, but that is followed closely by an attempt to understand the patient’s overall good—e.g., psychological good, good in terms of family and relations, spiritual good, and good in terms of the patient’s preceding life history and values. While ensuring the good of the woman is the primary aim, this is insufficient in itself, as the goods of fetus and others must also be considered (38).

The principles that apply in the case at hand are then evaluated, specifying what a given principle means in this case and balancing it against the moral claims of each of the others. In themselves, principles can become mere abstractions, perhaps even sterile nostrums for dealing with these complex ethical dilemmas. Therefore, virtue ethics, another bioethical approach that has received increased attention in recent years, addresses the nature of the relationship between patient and healer, with particular attention to the character of the physician (38). Pellegrino and Thomasma have presented a detailed analysis of how they interpret the virtues that are essential to medical practice. These virtues include phronesis, compassion, fidelity, trust, integrity, self-effacement, justice, fortitude, and temperance (50).

In any case, a consideration of the virtues and principles on the one hand, and guidelines recommendations and prior similar cases analysis on the other, provide more guidance for a right answer to bioethical dilemmas.

Finally, the guidelines recommendations should be accompanied by several steps that must take place in the “best ethical possible scenario”, in order to enhance the quality of the counseling and emotional support that are an essential part of management (Figure 2):