Kristel Van Calsteren1, 2
(1)
Department of Growth and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium
(2)
Department of Obstetrics & Gynaecology, Feto-Maternal Medicine, University Hospital Gasthuisberg Leuven, Leuven, Belgium
Kristel Van Calsteren
Email: kristel.vancalsteren@uzleuven.be
Keywords
Obstetrical careMaternal cancerOncological treatment
Introduction
Cancer is the second leading cause of death in women during the reproductive years and complicates between 1 in 1000 to 2000 pregnancies. In Europe, this number translates yearly into 3000–5000 new patients with cancer diagnosed during pregnancy. As women in developed societies defer childbearing to the third or fourth decade of life, and the incidence of most malignancies rises with increasing age, the rare coincidence of cancer and pregnancy is likely to become even more common. The most frequently encountered tumour types are identical to the group of nonpregnant women between 25 and 45 years old: breast cancer, haematological malignancies, dermatological malignancies and cervical cancer [1].
It is evident that in situations of life-threatening maternal diseases, priority is given to maternal health management. Nevertheless, cancer treatment during pregnancy includes risks for the fetus. Therefore, the pregnancy makes decisions on treatment and the treatment itself more complicated. On the other hand, terminating the pregnancy early to enable ‘standard oncological treatment’ includes pregnancy loss and iatrogenic prematurity of which the consequences are often underestimated in the oncological world.
Diagnosis of Cancer During Pregnancy
Pregnancy is a period in which women regularly consult a doctor and have physical exams, blood analysis and ultrasound examinations. This gives the opportunity for early diagnosis of major diseases like cancer. Hereby it is important to perform further technical examinations in case of a suspicious history and physical examination. A missed diagnosis or delayed treatment often poses a greater risk to the patient and her pregnancy than the hazard associated with ionizing radiation.
The International Commission on Radiological Protection (ICRP) recommends to keep the fetal radiation dose ‘as low as reasonably achievable (ALARA) principle’, with an absolute maximum dose of 100 mGy. At this dose threshold, no deterministic effects are expected, like fetal death, malformations or mental retardations, and the risk of stochastic effects, like cancer induction, is below 1 % [2].
To obtain an accurate diagnosis and staging, various diagnostic modalities are required that may have an impact on the developing fetus. In order to obtain all the required information on the stage of the disease, with the lowest achievable fetal radiation exposure, the optimal staging strategy should be discussed in a multidisciplinary setting with a maternal-fetal medicine specialist, medical and surgical oncologist, radiologist and nuclear medicine specialist.
Following diagnosis and staging, the stage of disease, gestational age and patient’s wishes will define the therapeutic options. The complex medical, ethical, psychological and religious issues arising in pregnant women with cancer demand care from a multidisciplinary team with maternal-fetal medicine specialists, oncologists, radiation oncologists, surgeons, paediatricians, geneticists and psychologists. On the other hand also the patient and her family should be actively involved in the decision-making process following adequate information and counselling [3, 4]. The relative rarity of pregnancy-associated cancer makes it hard to conduct large prospective studies to examine diagnostic, management and outcome issues. However, it is evident that curing the mother is the priority, but also the fetal health should be taken into consideration.
When Should We Deliver/Terminate the Pregnancy?
To determine the best timing for ending the pregnancy, the risks and benefits for the mother and the fetus should be balanced.
In order to obtain an optimal prognosis for the mother, unnecessary delay in treatment should be avoided and standard cancer treatment, defined as the treatment with the best outcome results in RCT in nonpregnant patients, should be applied. Standard cancer treatment includes surgery, systemic treatment (chemotherapy, targeted treatment) and radiotherapy or a combination of these. Hereby, slight modifications can be acceptable as long as these adaptations will not worsen the maternal outcome, e.g. some weeks delay in adjuvant radiotherapy to defer it till postpartum.
Pregnancy was shown not to have a negative impact on the maternal oncological outcome, except for melanoma [5]. Termination of pregnancy after a diagnosis of cancer does not seem to improve survival [6].
Therefore, the only medical indications for terminating the pregnancy are unacceptable high risks of the cancer treatment for the fetus and a very poor maternal medical condition and prognosis.
The risks for the fetus are defined in teratogenicity of cancer treatment and co-medication, in prematurity after preterm delivery and extremely rarely in fetal metastasis.
Teratogenicity of Cancer Treatment
Standard cancer treatment consists of surgery, systemic treatment (chemotherapy, targeted treatment) and radiotherapy.
Surgery is considered to be safe. The potential risk of fetal damage induced by cytotoxic treatment will largely depend on the exposure period in pregnancy. During the first 10 days post-conception (fertilization/implantation), a fetotoxic event will have an ‘all or nothing’ effect. When sufficient cells survive, the embryo will develop normally; otherwise, a miscarriage occurs. Between 10 days and 8 weeks after conception, cytotoxic therapy may interfere with organogenesis and result in congenital malformations. The potential for fetal damage varies depending on the type of treatment and dosages used. After single-agent chemotherapeutic treatment, 7–17 % malformations are seen; after combination schemes, the risk rises till 25 %. Excluding the folic acid antagonists, a risk of 6 % is reported [7]. After radiotherapy, fetal malformations are expected to occur from a threshold dose of 100 mGy [8]. The type of malformation depends on the timing of exposure in the embryological development. The most frequently described malformations are skeletal problems (face, limbs).
During the second and third trimesters of pregnancy, organogenesis is completed with the exception of the eyes, gonads and central nervous system. Consequently no major malformations are expected to be caused by cytotoxic treatment. Nevertheless, growth restriction, prematurity, intrauterine and neonatal death and haematopoietic suppression have been reported after exposure to chemotherapy or a fetal radiation dose exceeding the threshold of 100 mGy. Moreover, potential problems of neurodevelopmental delay, subfertility, carcinogenesis and genetic defects have to be considered on the long term [9–11].
In order to avoid problems associated with haematopoietic in the patient and neonate (bleeding, sepsis, anaemia) and to avoid drug accumulation in the fetus, an interval of 3 weeks should be respected between the last cycle of chemotherapy and the anticipated delivery [3, 12].
Studies evaluating the long-term outcome of children exposed to chemotherapeutics during the second and third trimesters of intrauterine life are hampered by small numbers and reduced follow-up time. Most recent studies do not show significant increase of congenital malformations or developmental impairment in these children [13–17]. However, it is accepted that the risks associated with fetal exposure to chemotherapeutics in utero are not limited to pre- and perinatal risks. Careful examination at birth but also systematic long-term follow-up of neurologic and psychomotor development is advisable for all children that underwent in utero exposition to chemotherapeutic agents or radiotherapy.
Experience with targeted therapy agents during pregnancy is limited. Nevertheless, their use in pregnancy has been associated with fetal complications. The use of hormonal agents such as selective oestrogen receptor modulators (SERMs) or the aromatase inhibitors in the treatment of breast cancer interfere with the hormonal situation of a normal pregnancy and should be avoided. They have been associated with vaginal bleeding, spontaneous abortion, birth defects including craniofacial malformations and ambiguous genitalia and fetal death [18]. Monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus. Exposure to these agents after the first gestational trimester has been linked to specific ‘on target’ effects, e.g. oligohydramnios with respiratory and renal failure after trastuzumab exposure and B-cell depletion after rituximab exposure [19].
On the other hand, small molecules like tyrosine kinase inhibitors (TKIs) can cross the placenta throughout the pregnancy period and therefore also can cause major congenital malformations [19].
Apart from the cytotoxic treatment, these women are exposed to supportive treatment agents, like painkillers, antiemetics, corticosteroids and GSF. For each group of supportive agents, drugs which are shown to be safe during pregnancy should be selected [20, 21]. The use of steroids deserves attention, since repeated antenatal exposure is associated with increased incidences of attention problems and higher rates of cerebral palsy [22]. In contrast to dexamethasone and betamethasone, methylprednisolone and hydrocortisone are extensively metabolized in the placenta and are therefore the preferred steroids to use during pregnancy, except to achieve fetal lung maturation.
Prematurity
In rare cases, the condition of the mother is deteriorating so rapidly that delivery needs to be expedited for maternal reasons. More often, a dilemma between the risks related to iatrogenic preterm birth and exposure to chemotherapy and radiotherapy arises at some point during pregnancy. As a result, a lot of these babies are delivered preterm.
Perinatal mortality and morbidity are known to decrease dramatically from 24 weeks onwards with every week that is gained in utero in good condition. For individual countries and regions, these figures can vary substantially. It therefore seems advisable that parents are informed based on the local or national statistics and include not only survival figures but also data on neonatal and long-term morbidity.
Preferably, delivery should not be performed before 35–37 weeks [21]. Prematurity, including late prematurity (34–37 weeks), is associated with general health problems and cognitive and emotional development disorders, on the short and on the long term [23, 24]. Therefore, maximal efforts should be made to avoid unnecessary prematurity in patients where cancer treatment can be given during pregnancy.
Fetal Metastasis
Documented reports of maternal malignancy metastases in the placenta are rare. Since the first description in 1866, less than 100 cases have been described. Most frequently reported tumour types are malignant melanoma, leukaemia and lymphoma, breast cancer and lung cancer. Proven maternal metastasis to the fetus is exceptional, with only 17 cases reported so far [25]. Despite this, each placenta should be thoroughly examined for metastasis, which, if present, should alert the clinician to monitor the infant for development of malignant disease.
How Should We Follow Up the Pregnancy?
In most cases, routine obstetrical follow-up is sufficient. However, one should be aware that the average age of these patients is increased compared to the normal obstetric population. Special attention is therefore required not only for the oncological condition of the patient but also for age-related pregnancy risks like hypertension, gestational diabetes and increased risk for fetal aneuploidy.
Before staging examinations or oncological treatment is started, fetal structural development and growth should be evaluated to exclude pre-existing anomalies [12]. Monthly a detailed fetal assessment should be performed by a maternal-fetal medicine specialist in order to follow up fetal growth and detect possible teratogenic effects.
Furthermore, special attention is required for preterm labour and fetal growth restriction [1]. Apart from the obstetrical follow-up for these complications, it is important to consider adequate painkilling, prompt treatment of complications as infections and anaemia and sufficient nutrient intake.
How Should We Deliver?
Like in the general population, there are several important advantages to opt for a vaginal birth in most of these patients including reduced blood loss, reduced operative risk, reduced infection risk, shorter duration of hospitalization and better preservation of reproductive future. This is especially important for patients with myelosuppression after cancer therapy. Moreover, the faster recovery after a vaginal delivery in comparison to caesarean section is important for women in need to start chemotherapy shortly after the delivery.
Despite this, a large number of patients are reported to deliver preterm by caesarean section. In some rare cases, like cancer metastasis to the long bones which increases the risk for fractures during labour precipitated by lithotomy position during labour and expulsion, a caesarean section has to be preferred. Active pushing can also be contraindicated in central nervous system tumours that cause increased intracranial pressure. Assisted vaginal delivery can then be safely offered in most cases. Although cervical intraepithelial neoplasia is not an indication for operative delivery, vaginal birth in women with cervical cancer can lead to fatal recurrences in the episiotomy scar. Operative delivery avoiding surgical trauma of the lower uterine part in order to prevent wound metastasis is therefore recommended in cervical cancer patients [21]. In patients operated for vulvar cancer during pregnancy, vulvar scarring and the risk for vulvar trauma can be an indication for caesarean section [21].
What Is Important in the Postpartum Period?
Oncological treatment can be started again within a week after an uncomplicated delivery.
As the postpartum period and malignancy are both risk factors for venous thromboembolism, prophylaxis should be considered after an operative delivery.
Advice on breastfeeding should be individualized since its safety depends on the type, site and timing of the treatment. Contraindications for breastfeeding are, e.g. the administration of chemotherapy within the peripartum period, radiotherapy of the breast and status after mastectomy.
In the postpartum period, special attention is required for the psychological condition of the patient. Often they keep very well during the pregnancy; ‘they fight for their child’. Once the baby is born, it seems much more difficult to deal with the cancer diagnosis and treatment for many women. The combination of normal postpartum difficulties like sleep deprivation and baby blues makes these patients extremely vulnerable in the postpartum period. It is important to talk about this before the delivery and make sure enough ‘helping hands’ are available.
Summary
Cancer during pregnancy is uncommon though not rare. Perinatologists play a crucial role when cancer staging and treatment is planned during pregnancy. A summary of the key obstetrical care measures is given in Table 6.1. A missed diagnosis or delayed treatment often poses a greater risk to the patient and her pregnancy than the hazard associated with ionizing radiation. The diagnosis and treatment of cancer in a pregnant woman is a clinical and ethical challenge for all medical care workers. The benefits and risks of the different diagnostic and therapeutic modalities should be carefully balanced for both the mother and the fetus in a multidisciplinary setting.
Table 6.1
Key obstetrical care measures that need to be performed for pregnant cancer patients
|
Gestational phase |
Obstetrical points of attention |
|
Preconception |
Perform a general and gynaecological history and physical exam with PAP smear. In case of clinical suspicions, delay the pregnancy until further technical examinations for diagnosis are performed |
|
Patients treated for cancer should be actively informed and prescribed anticonception |
|
|
Pregnancy follow-up |
Cancer diagnosis and treatment |
|
Consider the possibility of maternal cancer in case of suspicious history or findings at physical exam or prenatal ultrasound |
|
|
Do not delay technical exams and required treatment, but consider fetal safety: |
|
|
Maximum fetal radiation dose is 50–100 mGy |
|
|
Avoid chemotherapy in the first trimester |
|
|
Avoid targeted therapy |
|
|
Termination of pregnancy can be discussed for patients with a poor maternal prognosis and cancer diagnosis early in pregnancy |
|
|
Offer psychological support |
|
|
High-risk obstetrical follow-up |
|
|
Subgroups are at risk for preterm delivery and fetal growth restriction |
|
|
Fetal metastasis are extremely rare, but possible |
|
|
During chemotherapy treatment periods of haematopoietic suppression make the pregnant woman more vulnerable for complications of infections, anaemia and bleeding. Delivery should be avoided in these periods. These complications should be treated promptly |
|
|
Multiple (co-)medications are prescribed, consider optimal dose and fetal safety |
|
|
Delivery |
Timing |
|
Aim for delivery after 37 weeks (exception: deterioration of maternal or fetal condition) |
|
|
Keep a 3-week interval between the last chemotherapy cycle and delivery |
|
|
Mode: |
|
|
Preferably vaginal delivery (exception: cervical or vulvar cancer) |
|
|
Placenta: |
|
|
Should be examined for metastatic disease |
|
|
Postpartum |
Low molecular weight heparin should be considered |
|
Advice on breastfeeding should be individualized |
|
|
Offer psychological support |
We stress the need for large international collaborative studies on the outcome of the mother and children after cancer during pregnancy, to be able to control the outcomes for confounding factors, like prematurity and stage of disease at diagnosis. Ongoing studies on this subject are performed by, e.g. the International Network on Cancer, Infertility and Pregnancy (INCIP) and the German Breast Group (GBG).
References
1.
Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010;28:683–9.CrossRefPubMed
2.
Wrixon AD. New ICRP recommendations. J Radiol Prot. 2008;28:161–8.CrossRefPubMed
3.
Amant F, Deckers S, Van Calsteren K, et al. Breast cancer in pregnancy: recommendations of an international consensus meeting. Eur J Cancer. 2010;46:3158–68.CrossRefPubMed
4.
Eisinger F, Noizet A. Breast cancer and pregnancy: decision making and the point of view of the mother. Bull Cancer. 2002;89:755–7.PubMed
5.
Stensheim H, Moller B, van Dijk T, Fossa SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27:45–51.CrossRefPubMed
6.
Cardonick E, Dougherty R, Grana G, et al. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16:76–82.CrossRefPubMed
7.
Ebert U, Loffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther. 1997;74:207–20.PubMed
8.
Mazonakis M, Damilakis J, Theoharopoulos N, et al. Brain radiotherapy during pregnancy: an analysis of conceptus dose using anthropomorphic phantoms. Br J Radiol. 1999;72:274–8.CrossRefPubMed
9.
Kal HB, Struikmans H. Radiotherapy during pregnancy: fact and fiction. Lancet Oncol. 2005;6:328–33.CrossRefPubMed
10.
De Santis M, Di Gianantonio E, Straface G, et al. Ionizing radiations in pregnancy and teratogenesis: a review of literature. Reprod Toxicol. 2005;20:323–9.CrossRefPubMed
11.
Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004;5:283–91.CrossRefPubMed
12.
Loibl S, Schmidt A, Gentilini O, et al. Breast cancer diagnosed during pregnancy: adapting recent advances in breast cancer care for pregnant patients. JAMA Oncol. 2015;1(8):1145–53.CrossRefPubMed
13.
Hahn KM, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer. 2006;107:1219–26.CrossRefPubMed
14.
Aviles A, Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma. 2001;2:173–7.CrossRefPubMed
15.
Amant F, Vandenbroucke T, Verheecke M, et al. Pediatric outcome after maternal cancer diagnosed during pregnancy. N Engl J Med. 2015.
16.
Amant F, Van Calsteren K, Halaska MJ, et al. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol. 2012;13:256–64.CrossRefPubMed
17.
Ring AE, Smith IE, Jones A, et al. Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals. J Clin Oncol. 2005;23:4192–7.CrossRefPubMed
18.
Braems G, Denys H, De Wever O, et al. Use of tamoxifen before and during pregnancy. Oncologist. 2011;16:1547–51.CrossRefPubMedPubMedCentral
19.
Lambertini M, Peccatori FA, Azim Jr HA. Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev. 2015;41:301–9.CrossRefPubMed
20.
Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol. 1999;17:2971–94.PubMed
21.
Amant F, Van Calsteren K, Halaska MJ, et al. Gynecologic cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer. 2009;19 Suppl 1:S1–12.CrossRefPubMed
22.
Wapner R, Jobe AH. Controversy: antenatal steroids. Clin Perinatol. 2011;38:529–45.PubMedPubMedCentral
23.
Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008;359:262–73.CrossRefPubMed
24.
Lohaugen GC, Gramstad A, Evensen KA, et al. Cognitive profile in young adults born preterm at very low birthweight. Dev Med Child Neurol. 2010;52:1133–8.CrossRefPubMed
25.
Pavlidis N, Pentheroudakis G. Metastatic involvement of placenta and foetus in pregnant women with cancer. Recent Results Cancer Res. 2008;178:183–94.CrossRefPubMed