Pregnancy-associated Cancers: A Narrative Review

Pregnancy-associated


INTRODUCTION
Pregnancy-associated cancers are malignancies diagnosed during pregnancy or within one year of birth or abortion.Neoplasms diagnosed in the first year after the end of pregnancy are presumed to have originated in the previous months of pregnancy.
The clinical management of a pregnant patient with oncological disease is certainly a complex scenario due to the co-presence of the mother and the fetus: an accurate diagnosis and timely treatment may save the life of the mother, but may have irreparable consequences for the fetus.The psychological impact on the woman, the couple, and the family of an oncological disease during pregnancy is also significant.
It is therefore important to quantify this event and assess its impact.

METHODS
This is a narrative review of published data on cancer associated with pregnancy.The Scale for the Assessment of Narrative Review Articles (SANRA) was used to report and qualitatively assess the review [1].We conducted the review using a narrative review approach [2].PubMed was searched up to 1 December 2023 for relevant publications in English, focusing on, but not limited to, the use of the keywords listed.Key search terms were: pregnancy associated cancer OR ((cancer OR neoplasm OR chemotherapy OR malignancy) AND (pregnancy OR pregnant OR postpartum)).The most relevant articles providing useful information on definition, diagnosis, treatment options, and clinical management of pregnancyassociated cancers were selected.The bibliography was also analyzed to include articles that could have been missed.

Epidemiology
Cancer complicates approximately 1 in 1000 pregnancies, with about 25% diagnosed during pregnancy and the majority diagnosed after pregnancy [3].The literature on the incidence or prevalence of pregnancy-associated cancers is difficult to compare.Firstly, many studies have focused on a specific type of cancer.Secondly, there are many differences in study design, inclusion criteria, inconsistent followup periods, and different reference populations (i.e., pregnancies or births) between studies.
Pregnant women are more likely to experience cancers that are more common in women of reproductive age, with an incidence generally similar to that of women of the same age who are not pregnant [14]; the most commonly diagnosed is the breast cancer [3].Table 1 lists selected population-based studies regarding pregnancy-associated breast cancer; specifically, incidence rate, and the postpartum followup period are described.

Diagnostic challenge
Regardless of pregnancy status, early diagnosis of cancer is essential for successful treatment.The diagnosis of cancer in pregnancy is often delayed because it can be made complex by the fact that many of the symptoms of malignancy mimic the physiological changes of pregnancy, including nausea, breast changes, abdominal pain, anaemia, and fatigue.
The diagnosis of breast cacer during pregnancy represents a challenging situation for the patient and physicians, because variations in hormone levels can cause changes in the breast that can hide small new formations [27].Specifically, pregnancy increases breast density and nodularity, complicating clinical and radiological examinations [28].Although biopsy of a suspected breast lesion can be problematic due to the hypervascularisation and oedema typical of the gravid state, histopathology from core biopsies is the gold standard and should follow standard procedures as for non-pregnant women, but the pathologist needs to be aware of the pregnancy status to properly account for changes that may occur due to the physiology of the breast tissue during pregnancy [29].
The awareness of pregnancy-associated hyperpigmentation can also affect how potential malignant lesions or melanoma are interpreted and manifested.Therefore, any pigmented lesion that changes clinical or dermoscopic characteristics during pregnancy should be considered suspicious [30].
On the contrary, pregnancy favours early diagnosis of cervical cancer: women in this period are strictly monitored and the screening for this type of cancer is considered safe during pregnancy using correct sampling tool to minimize bleeding risk [31].However, also for cervical cancer, the physiological changes associated with pregnancy can lead to false-positive results, so the cytopathologist must be well informed; a Papanicolaou smear taken from a pregnant woman  2. American College of Obstetricians and Gynecologists (ACOG) guidelines for the use of x-rays, ultrasound, magnetic resonance imaging and radioisotopes during pregnancy and lactation.Source: [32,33] "Ultrasonography and magnetic resonance imaging (MRI) are not associated with risk and are the imaging techniques of choice for the pregnant patient, but they should be used prudently and only when use is expected to answer a relevant clinical question or otherwise provide medical benefit to the patient".
"With few exceptions, radiation exposure through radiography, computed tomography (CT) scan, or nuclear medicine imaging techniques is at a dose much lower than the exposure associated with fetal harm.If these techniques are necessary in addition to ultrasonography or MRI or are more readily available for the diagnosis in question, they should not be withheld from a pregnant patient".
"The use of gadolinium contrast with MRI should be limited; it may be used as a contrast agent in a pregnant woman only if it significantly improves diagnostic performance and is expected to improve fetal or maternal outcome".
"Breastfeeding should not be interrupted after gadolinium administration".may show squamous metaplasia or trophoblastic cells that could be mistaken for dysplasia [27].
Diagnosis by instrumental examination may have been delayed because exposure to procedures during pregnancy and lactation is avoided in the absence of a strong indication.There are, however, a large number of imaging techniques that can be used as diagnostic tools in pregnancy.Guidelines for the use of x-rays, ultrasound, magnetic resonance imaging, and radioisotopes during pregnancy and lactation are reported in Table 2.In the case of x-rays and nuclear medicine, the exposure of the patient and fetus to ionising radiation must be limited.Other diagnostic procedures such as incisional or excisional biopsies, endoscopies and bone marrow punctures can be performed safely [27,32,33].

Treatment options
1.A multidisciplinary approach A comprehensive assessment is needed when considering how best to manage a pregnant patient with cancer.This involves an analysis of the complex interplay between the progression of the tumour and the decision about whether to continue the pregnancy.This includes a thorough evaluation of the stage and type of cancer, its potential impact on the health of the mother and baby, and the therapies that can be given safely during pregnancy.Equally important is an understanding of how the continuation of the pregnancy may affect the approach to tumour treatment, taking into account the safety of the fetus and the potential need for adjustments to the treatment plan to ensure the best possible outcome for both mother and baby.
Management of this situation requires a joint strategy by a multidisciplinary team of obstetricians, oncologists, surgeons, radiologists, neonatologists, psychologists, and other specialists [34].It is therefore important that cancers during pregnancy are managed in referreal obstetrics hospitals togher with comprehensive cancer centers, with access to the resources and specialists needed to manage all aspects of treatment.[35].As for non-pregnant women, the approaches to cancer include: radiotherapy, chemotherapy, and surgery.The choice of treatment and its timing cannot be separated from the wishes of the mother and the couple, and is a challenge for each member of the medical and support team [34].

Surgical intervention
Planning surgery during pregnancy is based on assessing the potential risks for both progression of maternal disease and fetus health.Where indicated, the procedure can be performed at any time during the course of the pregnancy [36].Maternal surgery may result in preterm labour and altered uteroplacental perfusion with a resulting risk of hypoxia, brain injury, and fetal intrauterine death [37].Complications are more common with major abdominal or pelvic surgery due to the increased blood supply to the pelvis [36].However, a systematic review including pregnant women who underwent non-obstetric surgery found no increased rate of miscarriage or adverse birth outcomes compared with the general population [38].In the case of gynaecological malignancies, it is preferably performed in the early second trimester when the risk of miscarriage and the size of the uterus allows access [39].
With regard to anaesthesia, the US Food and Drug Administration suggests minimising the time under general anaesthesia, minimising the dose and concentration of the agent, and avoiding inhalational anaesthetics, propofol, and midazolam [40].The physiological changes of pregnancy require an adapted anaesthesiological approach with an additional safety margin to keep the blood pressure and the oxygenation of the mother as stable as possible [41].

Radiotherapy
Radiotherapy should be limited to a few patients; for others, chemotherapy allows safe deferral of radiotherapy [42].If strictly recommended, limited upper body use can be considered, as the uterus is out of the field and shielded from radiation, with care taken to protect the patient's abdomen with a shield [37,43].
Fetal exposure to radiotherapy depends on several factors, including gestational age (the fetus is most vulnerable during the first weeks of organogenesis), target dose (doses between 0.05 and 0.5 Gy are generally considered safe for the fetus during the second and third trimesters), the size of the radiation fields, and the distance from the edges of the fields to the fetus [44,45].
Careful planning using appropriate shielding techniques or other dose reduction techniques is therefore essential when treating a pregnant patient [46,47].
In the specific case of breast cancer, breastfeeding during radiotherapy is not recommended because the suckling effect of the infant may potentially increase radiotherapy-induced skin toxicity, leading to discomfort, skin breakdown, and infection [48].

Chemotherapy
The physiological changes induced by pregnancy may have an effect on the pharmacokinetics and pharmacodynamics, i.e. the absorption, distribution, metabolism, excretion and mechanism of action of the drug.These changes include an increase in plasma volume by approximately 50%, an increase in renal clearance and an increase in hepatic metabolism.The result is a reduction in the active concentration of the drug in comparison with the same dose in a nonpregnant woman of the same weight [49].
Over the past two decades, the use of chemotherapy during pregnancy has gradually increased [50].Most chemotherapy is discouraged in the first trimester as it may lead to increased morbidity, particularly congenital malformations [37,49,[51][52][53].The second and third trimester chemotherapy may be associated with intrauterine growth restriction, preterm delivery, low birth weight, and stillbirth [54].No consistent evidence of major effects on long-term fetal neurodevelopment has been reported.However, longer and more thorough follow-up is certainly needed to draw firm conclusions [52,55].
The mechanisms underlying the association between prenatal exposure to chemotherapy and adverse outcomes depend on several factors, including the duration and timing of exposure, the dose delivered to the embryo/fetus, and the disruption of cellular metabolism [56].
Not all chemotherapic drugs are dangerous [57,58].Table 3 shows the most commonly used chemotherapic treatment against breast cancer.
As for the potential effects on lactation, more than half of the women who underwent prenatal chemotherapy reported reduced milk production and breastfeeding difficulties, with the need to supplement infant feeding [59].
With evidence limited to a few case reports, little is known about the safety of chemotherapy for infants during breastfeeding.In addition to chemotherapy, cancer patients are usually given other drugs that can pass into breast milk and endanger the health of their babies.Despite the well known benefits for both mothers and their babies, breastfeeding during chemotherapy is discouraged, even though neonatal toxicity depends on the oral bioavailability of the drug, the pharmacokinetics of the newborn, and the amount of milk [60].

Management of pregnancy, delivery, and breastfeeding
The pregnancies in women with a diagnosis of malignancy are considered high-risk and should be monitored in a highly specialised centre with an effective multidisciplinary team.Regular ultrasound scans are required for early detection of malformations, assessment of fetal growth, placental flow, and amniotic fluid regularity [34,36,61,62].
If treatment of the neoplasm is planned, the precautions must be taken.In the case of surgery after 24 weeks, cardiotocographic monitoring of the fetus should be performed in order to ensure his well-being throughout the intervention.In addition, the woman needs to be made aware of the possible complications, so her consent needs to be obtained for an emergency caesarean section [34].During surgery, the patient should be placed in the left lateral decubitus position from 20 weeks' gestation to avoid compression of the inferior vena cava.Tocolytics should not be administered during surgery unless there is evidence of uterine contractions.Post-operative tocolytics may be considered for 48 hours from late second trimester if uterine manipulation is unavoidable [63].
In the case of chemotherapy, monitoring of fetal well-being is a requirement after each course of treatment.It is desirable to plan these treatments carefully according to gestational age.Chemotherapy is generally avoided in the first trimester and should not be administered later than 35 weeks and stopped approximately three weeks before delivery [34,41,49].This interval allows the drugs to be excreted by the fetus across the placenta.Otherwise, the drugs would remain in the infant's circulation [49].
Wherever possible, delivery should be planned and managed on the basis of obstetric indications, with fullterm delivery desirable to avoid the consequences of preterm birth [34,36,49,61].If a premature birth is necessary, it is important to ensure that the baby adapts well, for example by ensuring that the lungs mature through the administration of cortisone [34].In general, vaginal delivery is appropriate, but the mode of delivery needs to be assessed on a case-by-case basis, in particular depending on the type of cancer.For those that affect the pelvic-abdominal region, such as colorectal or gynaecological cancers, a caesarean section may be more appropriate.For cervical cancer, caesarean section is recommended if the tumor is more than 3 mm deep because of the risk of bleeding or obstructed labor [37].
Histological examination of the placenta should always be carried out after delivery; this is particularly important for leukaemia and melanoma [34,36,61].However, placental metastases are rare [36].
As for postpartum, a potentially safe combination

Chemotherapic options Evidence
FAC regimen (5-fluorouracil, doxorubicin, cyclophosphamide) FAC regimen was commolnly well tollerated.Doxorubicin and epirubicin were used either as single agents or in combination with 5-fluorouracil, in both cases well tollerated.
Short-term use of trastuzumab did not appear to put pregnancy at risk.Prolonged exposure was associated with adverse events.
AC regimen (doxorubicin, cyclophosphamide) FEC regimen (5-fluorouracil, epirubicin, cyclophosphamide) EC regimen (epirubicin, cyclophosphamide) Trastuzumab as HER2/neu targeted agent of breastfeeding and chemotherapy with minimal risk to the infant may be achieved by discarding the breast milk.It has been suggested that exposure to cyclophosphamide and paclitaxel is negligible when breast milk was discarded for as little as 2 days, whereas doxorubicin should be discarded for at least 6 days [64,65].

CONCLUSIONS
Over recent decades, there has been an increase in research into the feasibility and safety of oncological treatment during pregnancy, which has led to an increase in the number of ongoing pregnancies with timely treatment of the mother's cancer.However, a systematic approach is currently lacking due to the relative rarity of this situation.This will be useful in formulating evidence based guidelines for the management of cancer in pregnancy.

Table 1 .
Result from selected population-based studies about pregnancy-associated breast cancer

Table 3 .
Most common chemotherapic treatment during pregnancy