A multidisciplinary discussion is necessary to tackle a complex and infrequent medical problem such as cancer occurring during pregnancy. Pregnancy does not predispose to cancer, but cancers occurring in women of reproductive age are encountered during pregnancy. Ultrasonography and magnetic resonance imaging are the preferred staging examinations, but also a sentinel node staging procedure is possible during pregnancy. Standard cancer treatment is aimed for. Operations can safely be performed during pregnancy, but surgery of genital cancers can be challenging. The observation that chemotherapy administered during the second or third trimester of pregnancy, that is, after the period of organogenesis, has little effect on the long-term outcome of children adds to the therapeutic armamentarium during pregnancy. Cancer treatment during pregnancy adds in the continuation of the pregnancy and the prevention of prematurity.
Introduction
The estimated incidence of cancer diagnosed during pregnancy is one per 1000–2000 pregnancies. Breast cancer, hematologic cancers, melanoma, and cervical cancer are most frequently diagnosed, and they correspond to the most common types of malignancy for women in this age group. Pregnancies complicated by a maternal cancer diagnosis are high-risk pregnancies. The complex medical, ethical, psychological, and religious issues arising in pregnant women with cancer demand care from a multidisciplinary team with obstetricians, oncologists, radiation oncologists, surgeons, pediatricians, geneticists, psychologists, teratologists, and clinical pharmacologists. It is evident that curing the mother is the main priority. Correspondingly, the proposed treatment should adhere to standard treatment for nonpregnant patients. Recent studies have shown that oncologic treatment – with slight treatment modifications – is possible during an ongoing pregnancy, without jeopardizing fetal safety. Here, we aim to provide a concise update on current knowledge and recent research of cancer treatment during pregnancy.
Diagnosis and staging of cancer during pregnancy
Symptoms caused by a malignancy may mimic many common physiologic gestational symptoms such as nausea, fatigue, anemia, vaginal bleeding/discharge, abdominal discomfort/pain, or breast lumps. Ignoring or dismissing a warning sign can cause patient as well as doctor’s delay. All pregnant women deserve a careful clinical examination during checkups, and special attention is necessary for persisting/worsening complaints.
Staging examinations for cancer during pregnancy should be as comprehensive as for nonpregnant women, but they should only be performed if they change clinical practice. The most important issue of radiologic examinations during pregnancy is fetal radiation exposure. A prestaging multidisciplinary discussion is proposed in order to reduce unnecessary radiographic examinations . Ultrasonography and magnetic resonance imaging are preferred staging methods during pregnancy . If radiographic exams are deemed necessary, total fetal radiation exposure should be “as low as reasonably achievable” (ALARA), as radiation-induced effects are thought to be cumulative . A threshold dose of 100 mGy for the “deterministic” effects (e.g., lethality, malformations, and mental retardation), which are dose dependent, was determined by the American Association of Physicists in Medicine (AAPM) . X-ray and computed tomography generate the highest dosages, but they can often be performed safely with appropriate abdominal shielding. Table 1 shows the fetal irradiation doses for these diagnostic tests, reproduced from AAPM .
| Diagnostic test | Fetal irradiation dose (mGy) |
|---|---|
| RX thorax | 0.0006 |
| RX abdomen | 1.5–2.6 |
| CT thorax | 0.1–13 |
| CT abdomen | 8–30 |
| PET | 1.1–2.43 |
In the case of histopathologic examinations, gestational physiological hyperproliferative changes may influence tissue characteristics and thus the interpretation of tumor pathology. Therefore, the pathologist should be informed of the pregnant state . Furthermore, a tissue biopsy provides a more accurate diagnosis than fine-needle aspiration cytology.
Diagnosis and staging of cancer during pregnancy
Symptoms caused by a malignancy may mimic many common physiologic gestational symptoms such as nausea, fatigue, anemia, vaginal bleeding/discharge, abdominal discomfort/pain, or breast lumps. Ignoring or dismissing a warning sign can cause patient as well as doctor’s delay. All pregnant women deserve a careful clinical examination during checkups, and special attention is necessary for persisting/worsening complaints.
Staging examinations for cancer during pregnancy should be as comprehensive as for nonpregnant women, but they should only be performed if they change clinical practice. The most important issue of radiologic examinations during pregnancy is fetal radiation exposure. A prestaging multidisciplinary discussion is proposed in order to reduce unnecessary radiographic examinations . Ultrasonography and magnetic resonance imaging are preferred staging methods during pregnancy . If radiographic exams are deemed necessary, total fetal radiation exposure should be “as low as reasonably achievable” (ALARA), as radiation-induced effects are thought to be cumulative . A threshold dose of 100 mGy for the “deterministic” effects (e.g., lethality, malformations, and mental retardation), which are dose dependent, was determined by the American Association of Physicists in Medicine (AAPM) . X-ray and computed tomography generate the highest dosages, but they can often be performed safely with appropriate abdominal shielding. Table 1 shows the fetal irradiation doses for these diagnostic tests, reproduced from AAPM .
| Diagnostic test | Fetal irradiation dose (mGy) |
|---|---|
| RX thorax | 0.0006 |
| RX abdomen | 1.5–2.6 |
| CT thorax | 0.1–13 |
| CT abdomen | 8–30 |
| PET | 1.1–2.43 |
In the case of histopathologic examinations, gestational physiological hyperproliferative changes may influence tissue characteristics and thus the interpretation of tumor pathology. Therefore, the pathologist should be informed of the pregnant state . Furthermore, a tissue biopsy provides a more accurate diagnosis than fine-needle aspiration cytology.
Surgery during pregnancy
A vast experience of surgery during pregnancy for non-oncological reasons is available. Therefore, surgery is the least controversial type of oncologic treatment during pregnancy. Van Calsteren et al. found that surgery was performed in 65.7% of women with any cancer treatment during pregnancy . Surgery can be performed during all three trimesters. Anesthetic and surgical management during pregnancy require some modifications due to anatomic and physiologic changes and concerns about fetal safety. The basic objectives are as follows: (a) optimal surgical outcome, (b) maternal safety, (c) fetal safety, and (d) prevention of miscarriage/preterm labor.
Optimal surgical outcome
Apart from genital cancer, the applied surgical technique is similar to nonpregnant cancer patients. Indications for breast conserving surgery and sentinel node biopsy are the same as in nonpregnant patients. The technique of abdominal surgery requires special attention, because of the presence of the expanding uterus, which dislocates other internal organs depending on gestational age. For advanced-stage ovarian cancer, cytoreduction to no residual disease is not possible as the pouch of Douglas is virtually not accessible. Therefore, only a biopsy is taken during pregnancy, neoadjuvant chemotherapy is administered, and cytoreductive surgery is postponed until after pregnancy. In the case of cervical cancer, the pregnant uterus is involved, which is the most challenging situation. There is no standard treatment but several options exist according to the gestational age and stage of the disease. A detailed description of the rationale and indications for cervical cancer surgery is reported in a recent consensus statement . Conization, simple trachelectomy (large conization), and pelvic lymph node resection can be performed, especially until mid-second trimester. Radical trachelectomy during pregnancy is a hazardous procedure and accompanied with significant blood loss. The obstetric outcome is rather poor as six out of 19 described cases (32%) resulted in early abortions related to the procedure , and therefore this procedure is not recommended during pregnancy.
There are no randomized controlled trials that compare laparoscopy and laparotomy during pregnancy. In the case of laparotomy, a midline vertical incision is recommended for optimal exposure. In the case of laparoscopy, open laparoscopy (Hasson technique) is recommended to avoid trocar or Veress needle injury to the uterus . Port placement is important to avoid uterine perforation. The location of the first trocar should be at least 3–4 cm above the uterine fundus . Instead of the umbilicus, an alternate position in the supraumbilical midline or Palmer’s point (located 3 cm from the midline and 3 cm below the left rib cage) can be used. Depending on the procedure and experience of the surgeon, laparoscopy becomes technically difficult after 26–28 weeks of gestational age due to the gravid uterus, and laparotomy is preferred . There is an increased risk of fetal loss after laparoscopy for appendectomy (pooled relative risk of 1.91 (1.31–2.77)) , but it is unknown whether those results can be applied to a laparoscopic approach for oncologic surgery. Experts participating in a consensus meeting on gynecologic malignancies during pregnancy recommend four prerequisites for laparoscopy during pregnancy: a maximal laparoscopic procedure time of 90 min, a pneumoperitoneum with a maximal intra-abdominal pressure of 10–13 mmHg, open introduction, and an experienced surgeon .
Maternal safety
Physiologic changes that occur during pregnancy alter anesthetic management. Alveolar ventilation increases progressively to 70% at term. End-tidal PCO 2 falls to 33 mmHg by the third month of pregnancy and functional residual capacity decreases up to 20% at term. In addition, O 2 consumption increases significantly due to the O 2 requirements of the uterus, placenta, and fetus . Due to increased O 2 consumption and decreased functional residual capacity, apnea leads more rapidly to significant desaturation during pregnancy; therefore, thorough preoxygenation is critical. Requirements for volatile anesthetic agents decrease by about 30%, beginning in the first trimester . Dose adjustments of propofol are not necessary during pregnancy . Preoperative medication as a precaution to minimize the risk of aspiration pneumonitis is often given, although the actual risk of aspiration appears to be small. The rate of gastric emptying is not delayed during pregnancy . In a retrospective review of 51,086 first-trimester and 11,039 second-trimester pregnant patients undergoing deep sedation (without intubation) with propofol, no cases of perioperative pulmonary aspiration occurred .
Antibiotic prophylaxis depends on the specific procedure; cephalosporins, penicillins, erythromycin, and clindamycin can be safely administered during pregnancy.
Pregnancy, surgery, immobilization, and malignancy are all risk factors for the development of thromboembolic events. Therefore, prophylaxis with either unfractionated or low-molecular-weight heparin is advisable.
Fetal safety
Almost all commonly used anesthetics and premedicants are teratogenic in some animal studies. However, no anesthetic drug (premedicant, intravenous induction agent, inhalation agent, or local anesthetic) has been proven to be teratogenic in humans at any gestational age .
Fetal oxygenation is entirely dependent on maternal PaO 2 , oxygen-carrying capacity (hemoglobin content), oxygen affinity, and uteroplacental perfusion. Uterine blood flow will decrease in the case of maternal hypotension (due to deep general anesthesia, hypovolemia, or vena cava compression). Vena cava compression can be avoided by a left lateral tilt position . Maintaining normal maternal PaO 2 , PaCO 2 , and uterine blood flow is important; a stable maternal condition is the best guarantee for fetal well-being. One of the earliest signs of maternal distress is fetal distress, and the fetal condition can be critical by the time maternal hypotension manifests . Continuous fetal heart rate monitoring during surgery is therefore advisable when an intervention (e.g., cesarean section) is performed for fetal distress. This should be discussed preoperatively with the obstetrician and the parents, and it mainly depends on the gestational age, local policy, and parent’s consent. A fetal sleep pattern shows decreased variability, and it should be discerned from fetal distress. If the fetus is considered previable, it is generally sufficient to ascertain the fetal heart rate by Doppler or ultrasound before and after the procedure .
Prevention of miscarriage/preterm labor
Although data are limited, there is a consensus that tocolytic agents are indicated when manipulation of the pregnant uterus occurs . Otherwise, routine prophylactic tocolytics are not indicated but they should be considered perioperatively when signs of preterm labor are present, and in coordination with the obstetrician .
Postoperative analgesia
After surgery, adequate analgesia (paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and morphine) and antiemetics (metoclopramide, meclizine, alizapride, and ondansetron) can be prescribed . The pharmacologic action of NSAIDs involves prostaglandin inhibition in the patient; transplacental transfer is noted, but their action in fetal tissue is unknown. Hernandez et al. examined data from the National Birth Defects Prevention study (a multisite population-based, case–control study), and they found that NSAIDs during early pregnancy, most commonly ibuprofen, aspirin, and naproxen, were not associated with birth defects, although there were a few moderate associations with specific birth defects such as oral cleft, neural tube defect, anophthalmia/microphthalmia, pulmonary valve stenosis, amniotic bands/limb body wall defects, and transverse limb deficiencies . NSAIDs administered in the third trimester of pregnancy may be associated with premature closure of the ductus arteriosus and possible pulmonary hypertension in the neonate in 50–80% of cases .
Radiotherapy during pregnancy
Whether a pregnant patient can be irradiated for cancer treatment without expected fetal harm should be discussed with a radiophysicist. In most cases where a pregnancy is still early and an adequate distance exists between the radiation field and the fetus, that is, not exceeding the fetal irradiation dose of 100 mGy, radiotherapy during pregnancy is expected to be safe. Exposure to ionizing radiation is associated with an increased risk of biological effects to the fetus. Potential deterministic and stochastic effects have been reviewed in reports by the AAPM and the International Commission on Radiological Protection (IRCP) . They evaluated the results of animal studies, a series of human studies concerning the in utero risk of cancer induction and effects on the developing brain, and also the recent advances in the biological understanding of in utero developmental processes were considered. The expected effects and risks are described in Table 2 . The threshold doses for the “deterministic” effects were determined by in vitro and in vivo research. Risks were clearly induced when a fetal dose of 100 mGy was exceeded, uncertain between 50 and 100 mGy, and weak below 50 mGy. By contrast, no known threshold dose for the “stochastic” effects is determined . An estimation of the dose delivered to the fetus before treatment is necessary to assess the risk of radiation effects to the unborn child. There are three principal sources of dose outside the treated volume: (1) photon leakage through the treatment head of the machine, (2) radiation scattered from the collimators and beam modifiers, and (3) radiation scattered within the patient from the treatment beams . In addition, when the energy of the treatment photons exceeds 10 megaelectron volt (MeV), a substantial neutron dose can be expected.
| Gestational age (weeks) | Risk |
|---|---|
| Preimplantation (1) | Lethality a |
| Organogenesis (2–7) | Lethality, gross malformations a , growth retardation a , sterility, cataracts, other neuropathology, malignant disease |
| Early fetal (8–15) | Lethality, gross malformations, growth retardation, mental retardation a , sterility, cataracts, malignant disease |
| Midfetal (16–25) | Gross malformations, growth retardation, mental retardation, sterility, cataracts, malignant disease |
| Late fetal (>25) | Growth retardation, sterility, cataracts, malignant disease |
In the AAPM report, guidelines have been published on the estimation and reduction of the fetal dose. It is important to know the amount of photon leakage and the collimator scatter to the dose outside the field, because these components can be easily reduced by a factor of 2–4 by placing a shield over the critical area ( Fig. 1 ). However, the design of proper shielding is difficult, because it involves the use of heavy materials, causing important considerations towards the methods of supporting and the number of times in which it must be (re)placed. Besides this, the position and size of the fetus is also important to know before planning of radiation therapy. Towards the end of pregnancy, the fetus lies closer to the field and it could receive up to 10–15× the dose for the same treatment course . To consider this, the treatment plan can be adapted by changing field angles, reducing the field size, modifying the beam energy, using a machine with multileaf collimator (MLC), and placing the patient so the lower collimator defines the field edge nearest the fetus . It is important to calculate the fetal dose by measurements in a phantom before treatment is given. In a clinical setting, the Monte Carlo methodology can be used to evaluate and estimate the fetal dose . This computational procedure describes the calculation of the unshielded fetal absorbed dose for an average pregnant patient during the 3-, 6-, and 9-month gestational age. The models can be adopted for routine treatment planning, risk assessment, and the design of appropriate fetal shielding, in order to comply with the ALARA principle.
Few data on long-term follow-up of children exposed to radiation in utero are available . Although the numbers are small, the data are consistent and suggest that radiotherapy of upper body parts, before the third trimester and with shielding of the pregnancy, does not induce fetal harm.
Chemotherapy during pregnancy
The administration of chemotherapy is possible during the second and third trimester of pregnancy. Chemotherapy can be given from the 12 to 14th week of pregnancy until a gestational age of 35–37 weeks. Chemotherapy is relatively safe because of two reasons. Firstly, chemotherapy is administered after the first trimester, which is the period of organogenesis. Chemotherapy is associated with an all-or-nothing phenomenon during the implantation and induces malformations between the second and eighth week of pregnancy. This risk of malformation is estimated to be 10–20%. Some organs are more vulnerable including the eyes, the ears, the hematopoietic system, and the cerebral nervous system . Aviles et al. described 54 patients treated by chemotherapy during the first trimester of pregnancy without an increase of malformations and they explained this observation by a different renal and hepatic function and metabolism during the first trimester . However, the timing of chemotherapy administration was poorly documented . Therefore, chemotherapy is advised only after the 12th–14th week of pregnancy because of teratogenicity risks .
Secondly, the placenta is a barrier and protects the fetus. For all investigated drugs, lower fetal concentrations were encountered. The transfer of chemotherapy is analyzed in animal models and in vitro , and it depends on maternal pharmacokinetics, placental blood flow, and the physicochemical drug properties . The placenta is an active organ where placental transporters guide the transplacental passage of drugs. This passage can be low (paclitaxel, 0–1%), intermediate (anthracyclines, 5–7%), or high (carboplatin, 60%) . Although most cytotoxic drugs can be used during pregnancy, trastuzumab (Herceptin°) crosses the placenta and binds the Her-2 receptors of kidney epithelium, resulting in reduced amniotic fluid, lung hypoplasia, and fetal death . Currently, no guidelines exist regarding chemotherapy dosages during pregnancy and the same dosages are used for nonpregnant and pregnant patients. If corticosteroids are administered as co-medication, methylprednisolone is preferred over dexa/betamethasone as placental metabolization results in less transplacental transfer .
The knowledge that chemotherapy can be used during pregnancy has three clinical implications. Firstly, the need for chemotherapy is not a reason to terminate the pregnancy. Secondly, the potential to administer chemotherapy allows a timely maternal treatment without delay. Thirdly, the use of chemotherapy during pregnancy adds in the prevention of iatrogenic prematurity. Despite this, more children need to be followed up for a longer duration in order to provide more solid safety data. The different treatment options during pregnancy are presented in Table 3 .
