Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 61-79, February 2010

Gynaecologic cancer complicating pregnancy: An overview☆

  • Frédéric Amant, MD, PhD (Professor Gynaecological Oncology)

      Affiliations

    • Obstetrics and Gynaecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
    • Corresponding Author InformationCorresponding author. Tel.: +32 16 34 42 52; Fax: +32 16 34 46 29.
    • ,
  • Lieselot Brepoels, MD, PhD (Trainee Nuclear Medicine)

      Affiliations

    • Nuclear Medicine, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
    • ,
  • Michael J. Halaska, MD, PhD (Gynaecological Oncologist)

      Affiliations

    • Obstetrics and Gynaecology, Charles University in Prague, 2nd Medical Faculty, Czech Republic
    • ,
  • Mina Mhallem Gziri, MD (Gynaecologist)

      Affiliations

    • Obstetrics and Gynaecology, Université Catholique de Louvain, Belgium
    • ,
  • Kristel Van Calsteren, MD (Research Fellow Gynaecological Oncology)

      Affiliations

    • Obstetrics and Gynaecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium

published online 25 August 2009.

Article Outline

Cancer complicating pregnancy endangers two lives. Any approach should look at both maternal and foetal safety. Maternal prognosis will not improve by terminating the pregnancy. Imaging for staging purposes is possible, and sonar and magnetic resonance imaging are the preferred examinations. Abdominopelvic computed tomography exposes the foetus to the highest doses radiation and should be avoided.

Provided a thorough maternal monitoring to ensure a stable uteroplacental blood flow and foetal oxygenation, surgical techniques that are used in non-pregnant patients are also safe for pregnant patients. Radiotherapy of the upper part of the body is possible during pregnancy, but during the third trimester the close distance may put the foetus at risk. Chemotherapy during the second or third trimester can be administered without increasing the incidence of congenital malformations. A systematic analysis, especially on the long-term outcome of the offspring after cancer treatment during pregnancy is still lacking.

Here, we present a summary of issues related to the diagnosis and treatment of gynaecological malignancies during pregnancy. Firstly, we describe general diagnostic and cancer-treatment-related problems. In the second part, organ pathology including breast, cervical, ovarian, endometrial and vulvar cancer is discussed.

Keywords: cancer, pregnancy, radiotherapy, surgery, chemotherapy, neonatal

 

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Introduction 

Obstetrical health-care workers focus on both the maternal and foetal condition. With regard to foetal safety, different levels of protection can be identified. Pregnant women are advised to take as little medication as possible and to seek medical advice when treatment is necessary. Most medications are not tested in pregnant women and hence contraindicated during pregnancy, unless strictly needed. Pregnant women receive dietary advice since ingested micro-organisms may cross the placenta and may interfere with the foetal development. Some pregnant women who work in laboratory conditions need to change work given the potential toxic effect of the environment and solvents in particular. Foetal safety is a permanent concern.

This observation has important implications for cancer treatment during pregnancy. For a long time, oncological treatment modalities were considered incompatible with a normal foetal development. Termination of pregnancy, delayed treatment or preterm delivery avoiding cancer treatment during pregnancy, were frequently applied. However, delayed oncological treatment might harm the mother. Prematurity on its own may compromise the neonatal and long-term outcome of the child.

In the meantime, based on case reports and little series, clinicians have gained more experience. From this, it is clear that chemotherapy or radiotherapy initiated after the first trimester is reassuring with regard to the neonatal outcome.*1, 2 Furthermore, the maternal outcome is reassuring. A recent population-based study suggests that the prognosis for cancer diagnosed during pregnancy is not worse.3 These reassuring data for both the mother and foetus suggest that more pregnant women with cancer will be treated in the future.

Cancer in pregnancy is an uncommon problem diagnosed in about one in a 1000 pregnancies.*4, 5 In most developed countries, maternal age increases and as for most cancer the incidence rises with increasing age, it is expected that this will lead to an increased incidence of cancer complicating pregnancy.

Assessing 215 cancer cases during pregnancy in Belgium, the Netherlands and Czech Republic, breast cancer (46%) and haematological malignancies (18%) were most frequently diagnosed during pregnancy164 When pre-invasive cervical disease is included, cervical cancer is the second most common oncological disease entity during pregnancy.4 Cancers occurring less frequent during pregnancy include malignant melanoma, brain tumours, thyroid cancer, ovarian cancer and colon cancer*4, 5, *164

The purpose of this review is firstly to provide an overview on cancer-treatment-related issues during pregnancy. In the second part, we focus on gynaecological organ pathology, including breast cancer.

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Radiation exposure during pregnancy 

There is hesitation to perform diagnostic radiological or radionuclide scans in pregnant patients. However, if a scan is medically indicated for the benefit of the mother or the unborn child, there is no reason to withhold these exams during pregnancy. A missed diagnosis or delayed treatment often poses a greater risk to the patient and her pregnancy than the hazard associated with ionising radiation. However, there are some important concepts concerning radioprotection to be kept in mind during the decision making.

Basics of radiation exposure 

Damage by ionising radiation is caused by deposition of energy to tissue. This exposure is expressed by several units which reflect different concepts in this process. The amount of radiation to which an individual is exposed is expressed in becquerel (Bq) or curie (Ci). The absorbed energy in tissue as a result of radiation is expressed as gray (Gy), and when also the kind of radiation is taken into account, this is expressed in sievert (Sv). Older, not in the international system of units, integrated terms such as rad and rem, are replaced by Gy and Sv, respectively, (100rad=1Gy, 100rem=1Sv). In a figurative description, radiation can be compared as fruits falling from a tree. Becquerel stands for the amount of fruit falling, gray as the energy deposed on the person under the tree and sievert as the resulting bruises of the person.

It is important to note that some organs are more radiosensitive than are others. The law of Bergonie and Tribondeau states that cells are more radiosensitive if they have a high division rate, a long dividing future and a low differentiation level, which is, in general, the case in foetal tissue.6 Consequently, radiation-induced biological effects are directly related to the stage of gestation: the earlier in stage, the more detrimental the expected effects (Table 1).

Table 1. Potential effects of radiation in relation to gestation stage (adapted from Pavlidis et al.4).
StagePeriodAdverse effect that can occufr
Preimplantation/immediate postimplantationFrom conception to day 9–10Lethal, if not lethal the fetus will recover completely
Early organogenesisWeeks 2–6Teratogenesis, growth retardation
Late organogenesis/early fetal periodWeeks 12–16Mental and growth retardation, microcephaly
Late fetal stageFrom weeks 20–25 to birthSterility, malignancies, genetic defects

Biological effects of radiation in humans 

There are two categories of radiation-related effects in humans. ‘Deterministic effects’ occur short after a considerable amount of radiation. Once a certain threshold is exceeded, they will always be observed and there is generally no doubt that they were caused by radiation exposure. Typical examples of these effects in the unborn child are foetal death, physical deformities, microcephaly and mental retardation, which occur by a high radiation dose to the undifferentiated and rapid dividing foetal tissues. These effects can be expected once above a certain threshold of radiation, and the magnitude of the effect increases with dose (Table 2). However, thresholds at which these effects occur are much higher than those delivered to a foetus from the vast majority of diagnostic procedures.

Table 2. Radiation dose effect on foetal life (adapted from Pavlidis et al.4).
Dose (mGy)Effect on fetus
<100No deterministic effects, only minor risk of stochastic effects
100–150Increased risk
2.500Malformations in most cases
>30.000Abortion

‘Stochastic effects’ are probabilistic since they may or may not occur in any given exposed individual. They generally manifest many years later (the so-called ‘late’ effects) and cannot definitively be associated to the radiation exposure. Examples of these effects include cancer induction and genetic effects (in the offspring of irradiated individuals). These effects do not occur in relation to a certain threshold, but it is the probability of the effect that increases with administered dose. Therefore, even the lowest dose may provoke them, although with a smaller probability compared to a high radiation dose.

Because a radiation-induced cancer is indistinguishable from a spontaneous cancer (high background risk), the perception of teratogenic risk by many clinicians is higher than the actual risk.7 The fact that these effects are not threshold related forms the basis for one of the major principles in radioprotection: the ALARA principle, which stands for ‘As Low As Reasonably Achievable’. This concept means that the administered radiation dose should be kept as low as possible (as well for the patient, the foetus and the environment), but certainly without impairment of the diagnostic value.

It is important to keep in mind that most of the risk calculations of radiation exposure are based on population studies in survivors of the Japanese atomic bombing assuming a linear dose–response relationship. However, these populations are subject to a large variety of uncertainties and since these persons, in general, were subject to high radiation doses, extrapolation of these results to low exposure doses should be regarded with great reservations, not at least because high-dose exposure has significantly different biological effects than low radiation doses because of intracellular repair mechanisms.

In general, a foetal exposure of less than 100mSv is considered to provoke no deterministic effects and has an associated risk of stochastical effects of <1%8, which does not justify termination of pregnancy, according to the recommendations of the International Commission on Radiological Protection (ICRP-84).9 Therefore, termination of pregnancy for reasons of diagnostic radiation exposure is virtually never indicated.

Nuclear medicine 

Nuclear medicine studies use a radionuclide bound to a chemical agent, which defines the distribution of the radiopharmaceutical tracer. The effect of these substances on the foetus depends upon the biokinetic behaviour of the tracer, placental permeability, foetal distribution, tissue affinity and the half-life, dose and type of radiation emitted.

Stabin et al. developed a series of phantoms for the adult female at three stages of pregnancy (3-month, 6-month and 9-month pregnant) by modelling the changes to the uterus, intestines, bladder and other organs.10 These phantoms allow the estimation of absorbed doses to the female organs as well as the dose to the foetus and placenta per unit activity of an administered radiopharmaceutical.11

For most radioisotopes, the main fraction of foetal exposure evokes from proximity to radionuclides excreted into the maternal bladder. Maternal hydration and frequent voiding can reduce this exposure and the use of a bladder catheter may be indicated when the radiopharmaceutical follows renal excretion and when a scan demands prolonged immobilisation (e.g., positron emission tomography (PET)).

Often the administered dose of the radiopharmaceutical can be reduced compared to the standard dose, but this may demand a prolonged acquisition time to preserve diagnostic quality of the images. In the pregnant patient, this option should certainly be discussed with the nuclear medicine physician. The main nuclear examinations, which are indicated for during pregnancy, are PET, pulmonary ventilation–perfusion, and sentinel node mapping.

The (ventilation–)perfusion scan for suspected pulmonary embolus is among the most common nuclear medicine studies obtained in pregnant women. By limiting the administered activity to 80MBq 99mTc-macroaggregates (half the standard dose), one can limit radiation dose to a 6-month-old foetus to 0.4mSv. The estimated risk for fatal paediatric cancer in this dose is less than 1/100 000, compared with a normal background incidence of 80/100 000. The risk of undiagnosed pulmonary embolism for mother and foetus is much higher. Pulmonary spiral computer tomography (CT) gives, in general, a lower foetal dose, but this advantage is largely outnumbered by the increased maternal risk of breast cancer due to the much higher radiation dose to the sensitive breast tissue.

A second frequently indicated procedure is sentinel node mapping in breast cancer patients. With the standard dose of 40MBq 99mTc-nanocolloid used for a 1-day protocol in our centre and taking into account the distance between the injection site and the foetus, radiation exposure to the foetus is negligible and expected to be lower than 0.05mSv. Therefore, pregnancy may not be a reason for not performing this procedure.

Qualitative bone scanning demands a higher dose of the radiopharmaceutical (about 740MBq 99mTc-MDP) compared to previously mentioned procedures, leading to an estimated foetal dose of about 2mSv. Since this technique is often used in the standard workup of patients with a low pre-test probability for bone metastases, and, consequently, a change in patient management is unlikely in most cases, this radiation exposure has to be judged against the clinical benefit, although this dose is still limited in terms of risk estimates. Magnetic resonance imaging (MRI) can be used instead.

Positron emission tomography scan (18F-PET) is a highly sensitive technique for the detection of tumoural lesions. Since PET technology is based on positron–electron annihilation and the detection of rather high-energy photons, the biological effect of the radiopharmaceuticals used is more significant. Optimisation of the scanning protocol is, therefore, even more crucial, which should also include an evaluation of the protocol and necessity of the concurrent CT scan in case of a combined PET/CT examination. A standard 18F-FDG-PET examination results in a dose exposure of a 6-month-old foetus of 5–6mSv, which is still acceptable in many indications in view of the important information PET can add to the staging of, for example, lymphoma. In any case, consultation of the nuclear medicine physician and medical physicist, prior to the pregnant patient presenting herself to the nuclear department, allows taking some simple measures which can significantly limit the foetal exposure by limiting the dose of the radiopharmaceutical, additional maternal hydration and the use of a bladder catheter.

Some radionuclides will appear in breast milk. For these radionuclides, it is recommended to wait for 10 half-lives of the radionuclide before resuming nursing (i.e., 10×6h for 99mTc and 10×2h for 18F-PET) after which no significant amount of the radionuclide would be present. During this time delay, pumped breast milk can be safely stored for later use, depending on the radiopharmaceutical used.

Following the recommendations of the International Atomic Energy Agency (IAEA), breastfeeding should not be discontinued after the administration of 99mTc-macro-aggregates (perfusion scintigraphy) or 99mTc-MDP (bone scan).12, 13

At this time point, there is no clinical indication that urges for radionuclide therapy during pregnancy. In any case, foetal exposure by radionuclide therapy is expected to exceed the threshold for deterministic effects, and should therefore be avoided and postponed till after delivery of the baby.

X-ray imaging 

If there is already a large variability in dose exposure for nuclear medicine examinations, this is even more the case for radiological procedures. The estimated foetal exposure for some common imaging procedures is listed in Table 3.14

Table 3. Approximate foetal doses from common radiological diagnostic procedures in the United Kingdom according to the International Atomic Energy Agency.
Mean (mGy)Maximum (mGy)
Conventional X ray examinations
Abdomen1.44.2
Chest<0.01<0.01
Intravenous urogram1.710
Lumbar spine1.710
Pelvis1.14
Skull<0.01<0.01
Thoracic spine<0.01<0.01

Fluoroscopic examinations
Barium meal (UGI)1.15.8
Barium enema6.824

Computed tomography
Abdomen8.049
Chest0.060.96
Head<0.005<0.005
Lumbar spine2.48.6
Pelvis2579

Medically indicated diagnostic studies remote from the foetus (e.g., radiographs of the chest or extremities) can be safely executed at any time during pregnancy with current radiological equipment. Under normal operating conditions, these examinations result in very low doses of <1mGy to the foetus. The risk of not making the diagnosis is generally greater than the radiation risk involved.

If an examination is at the high end of the diagnostic dose range, and the foetus is in or near the radiation beam, the examination should be tailored to the clinical indication, and the number of image acquisitions should be minimised.

Some of the methods for minimising the dose to the foetus include restricting the X-ray beam size, reduction of mAs, adapting the direction of the primary beam, selecting acquisition parameters and keeping the exposure time as low as possible. For direct exposures, a lead shield might cover the area being imaged. However, if the foetus is not in the direct X-ray field, this has little effect because the radiation exposure to the foetus predominantly arises from scattered radiation within the patient, but it can be reassuring for the patient.

Computed tomography (CT) of the abdomen and pelvis are by far the examinations with the highest radiation exposure to the foetus, although data from the literature also show a high variability for these procedures (Table 3). Where possible, they should be replaced by ultrasound. In any case, radiation exposure should be carefully balanced against the potential change of patient management and patient's benefit.

Iodinated contrast materials cross the placenta and can produce transient effects on the developing foetal thyroid gland, although clinical sequelae from brief exposures have not been reported. Women who are breastfeeding should avoid nursing for 24h after intravenous administration of contrast material because the iodinated contrast is excreted into breast milk.

Ultrasound 

No biological effects have been documented from diagnostic ultrasound in the pregnant patient despite intensive use over the past 3 decades.

Magnetic resonance imaging (MRI) 

Although there is no conclusive evidence that the use of clinical MRI produces deleterious effects on human embryos or foetuses, the safety of MRI procedures during pregnancy has not been definitively proven. MRI is not recommended during the first trimester because the developing embryo is susceptible to injury from various physical agents.15 Possible biological effects at the cellular level include the induction of local electric fields and currents from the static and time-varying magnetic fields, and tissue and cellular heating due to radio-frequency radiation.

For some indications, MRI is the preferred diagnostic modality because it may provide better images than ultrasonography while avoiding the ionising radiation of CT. A typical example in oncology is the evaluation of tumour volumes and lymph node metastasis in the pelvic region where MRI has the advantage of three-dimensional imaging and excellent tissue contrast.

The use of iodinated and gadolinium contrast media 

The principal anxiety for the safety of the foetus relates to exposure to ionising radiation; however, the potential for effects related to the administered contrast agents should also be considered. Both iodinated and gadolinium contrast agents have been shown to permeate through the placenta and enter the foetal blood and amniotic fluid, although no mutagenic or teratogenic effects have been described after administration.

The most significant potential harmful effect of iodinated contrast media during pregnancy is depression of foetal thyroid function, which is caused by free iodide in the contrast solution. Hypothyroidism was reported after amniography16 and was associated with the use of lipid-soluble contrast media. More recently used water-soluble contrast media contain a very small amount of free iodine and have not shown this effect until now. However, there are no conclusive experimental data to indicate how much of this free iodide crosses the placenta and how long it remains in the foetus. Probably, free iodide in the foetus diffuses out across the placenta rapidly, back to the maternal circulation, and the foetal thyroid is only exposed for a short period of time. Although some early animal experiments pointed to spontaneous abortion and teratogenic effects due to the long half-life of gadolinium, no effect on the foetus was confirmed in the more recent studies.

Because of the uncertainty about the use of contrast media, the members of the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR) published recommendations on the use of contrast agents during pregnancy and breastfeeding.17 They recommend, in circumstances where radiographic examination is essential, that iodinated contrast media may be given to the pregnant mother. In this case, neonatal thyroid function should be checked during the first week after birth. When MRI examination is necessary, gadolinium media may be administered, and no neonatal tests are necessary.

The miniscule amounts of contrast agents which reach the milk are significantly lesser than the amounts administered to neonates during imaging procedures and are insufficient to disrupt breastfeeding after administration of contrast agents.

Radiotherapy 

In contrast to diagnostic procedures, therapeutic procedures in general result in much higher radiation exposure to the foetus, which can result in significant foetal harm. There are no hard rules, but the decisions made should be carefully discussed with the patient, family and the treating oncologist and radiotherapy physicist.

Many factors must be considered, such as the stage, location and aggressiveness of the tumour, the impact of delaying therapy, stage of pregnancy and when the baby could be safely delivered, as well as legal and moral issues. The first consideration is whether the treatment can be postponed till the foetus is at a later gestation age. Where possible, radiotherapy should be avoided for the benefit of the foetus.

The paramount factor in foetal dose is the distance from the foetus to the edge of the radiation field. Regardless of protective measures, pelvic radiotherapy in a pregnant patient almost always results in severe consequences for the foetus, and most likely foetal death. If cervical cancer is diagnosed in the first trimester, in most cases, termination of the pregnancy is indicated. In case of early stage cervical cancer or later during pregnancy, often a delay in treatment should be recommended until the baby can be safely delivered.

By contrast, when the radiation field is at a further distance from the foetus, radiotherapy may still be indicated during pregnancy; for example, in patients with early-stage Hodgkin's lymphoma, currently there is no evidence for the teratogenic effect of supradiaphragmatic radiotherapy.18 When the decision is made that radiotherapy is necessary during pregnancy, it is important to calculate the dose to the foetus before treatment is given. The American Association of Physicists in Medicine (AAPM) published guidelines on the estimation and reduction of the foetal dose.19 These guidelines include estimations of the foetal dose using phantom measurements, shielding and modifications to the treatment plan. If these options are not available in the institution, the patient should be referred to another institution.

In any case, the option of radiotherapy during pregnancy should always be discussed by a broad multidisciplinary team of specialists.

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Surgery during pregnancy 

During pregnancy, surgery can be performed safely by skilled surgeons and anaesthetists.20, 21 Nevertheless, considering the enlarged uterus, pelvic surgery is more challenging during pregnancy as the access is impaired and an oncologically optimum resection is technically more difficult to achieve.

Potential surgery-related risks to the foetus include exposure to anaesthetic agents, but more important are intra- and postoperative complications. Although the use of most anaesthetic agents is considered safe for the developing foetus21, hypoxia, hypotension, hypoglycaemia, fever, pain, infections or thrombosis can have serious adverse effects on foetal wellbeing. Therefore, an adequate maternal monitoring, considering the physiological adaptation of pregnancy, is crucial during surgery. To prevent caval compression, pregnant patients should be positioned in left lateral tilt. During abdominal/pelvic surgery, special care should be taken when the uterus is manipulated or retracted, because it is essential to avoid impairment of the uteroplacental blood flow and separation of the placenta.

In the postoperative period, an adequate analgesia is of great importance since pain can induce preterm contractions. Thrombosis prophylaxis and antibiotic prophylaxis is recommended as well.

For non-emergent surgeries, it is recommended to perform the surgery in the second trimester of pregnancy, because the risk of inducing abortion or preterm labour is the least, and, for abdominal surgeries, the uterus volume technically still allows intra-abdominal interventions.21

Cohen-Kerem et al. reviewed over 12 000 cases of non-obstetric surgery during pregnancy, which showed that surgery does not increase the risk of miscarriage and congenital anomalies.22 Only in cases of peritonitis, the foetal loss rate was increased. Furthermore, these data suggested that surgery might slightly increase the risk of preterm delivery, especially after appendectomy. However, the numbers are difficult to interpret since no comparison was made with a normal pregnant population.

Besides open surgery, laparoscopic surgery during pregnancy is also considered safe and effective.23 The CO2 pneumo-peritoneum and CO production during electro-coagulation do not seem to be hazardous to the foetus as long as the maximal pressure (normal: 10–13mmHg, max.: 15mmHg) and operation time (25–90min) are adhered to.23, 24, 25, 26, 27 Open laparoscopy (opening of the peritoneum under direct visualisation instead of using the Verres needle) is mandatory to avoid uterine perforation. Rizzo et al. described 11 cases of laparoscopic surgery during pregnancy between 16 and 28 weeks of pregnancy.24 Surgery was uneventful and the children were healthy when examined 1–6 years after surgery. The safety of laparoscopy was confirmed by Mathevet et al. and Yuen et al. in 48 and 67 patients, respectively.25, 26

When pelvic surgery is planned between 24 and 34 weeks of gestation, the administration of corticoids (dexamethasone or betamethasone) for foetal lung maturation is recommended. Whether or not to monitor the foetus during surgery, if at all technically feasible, should be discussed with the obstetrician and neonatologist.21 As no data are available supporting the benefit of systematic use of tocolytic drugs, this should only be considered in case of contractions.

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Chemotherapy and trastuzumab during pregnancy 

Valid data on transplacental transport of chemotherapy are lacking. However, reports on foetal death, congenital transformations, neonatal alopecia and neonatal neutro/thrombocytopenia suggest that at least a fraction of chemotherapy crosses the placenta and reaches the foetus.

The effect of the administration of chemotherapeutics will depend on the drug scheme (i.e., type of drugs, dose and duration). Folic acid antagonists including methotrexate carry the highest risk of malformations.1 Excluding folic acid antagonists, the use of cytotoxic drugs during organogenesis will double the risk of foetal malformations (6%).

Because after organogenesis, the eyes, genitals, haematopoietic system and the central nervous system remain vulnerable, it is recommended to wait until 14 weeks to initiate chemotherapy. During the second and third trimesters (foetal phase), chemotherapy can be administered relatively safely.1

The anti-tumour antibiotics, doxorubicin and epirubicin, can be used in pregnancy without risking foetal development*1, 28, but foetal death has been reported after idarubicin exposure.28 It is explained by the more lipophylic properties of idarubicin and the higher affinity for DNA.29 Idarubicin is therefore best avoided during pregnancy.1 The alkylating agents, cyclophosphamide, ciplatin and carboplatin, are also relatively safe to be administered.

Based on 37 reported cases, we calculate that cisplatin exposure resulted in moderate bilateral hearing loss in one (2.7%) and ventriculomegaly e causa ignota in another (2.7%).30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 This latter patient received one cycle of bleomycin, cisplatin and etoposide at a gestational age of 26 weeks. Apart from significant manipulation of the uterus to remove the uterus and the development of pelvic haematoma requiring blood transfusion that might have been associated with foetal hypoxia, a direct neurotoxic effect must be considered.32 In another case, maternal sepsis following bleomycin, cisplatin and etoposide administration occurred, resulting in pre-term labour.44 The premature neonate (1190g) developed respiratory distress syndrome, myelosuppression, hearing impairment and alopecia. Although cisplatin might have contributed to the sensorineural hearing loss, prematurity and the postnatal treatment with gentamycin were the confounding factors. Taking these into account, it was observed that administration of cisplatin and cisplatin-containing regimens during pregnancy resulted in normal neurological development and absence of congenital anomalies in 35 cases (95%). It should be noted that follow-up of the offspring was always short.

Carboplatin has been administered during pregnancy in eight cases (of which four in association with paclitaxel), and a normal neonatal outcome was noted in each.*1, 47, 48

Twenty-one case reports were found on the use of taxanes during pregnancy: 14 on paclitaxel46, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 and seven on docetaxel.39, 59, 60, 61, 62, 63 One case of hydrocephalus was described although this patient received docetaxel in combination with doxorubicin and cyclophosphamide. The outcome of the foetus after 28 months was normal.62

At least nine cases of a combination of bleomycin, cisplatin and etoposide during pregnancy for treatment of germ cell tumours have been described.32, 35, 36, 37, 41, 64 Although reports describe a normal neonatal outcome, one child with a significant ventriculomegaly with cerebral atrophy was born (see discussion above).32 Based on this case of poor neonatal outcome, Hubalek et al. suggested using paclitaxel and carboplatin for stage III dysgerminoma.52

Trastuzumab has been used in eight cases.65, 66 Transient anhydramnion or oligohydramnios (resolved 7 weeks after the last course of chemotherapy) was observed in patients treated by trastuzumab with docetaxel during the second trimester63, by trastuzumab with paclitaxel49 and by trastuzumab alone67 as well when administered during the first trimester.66 In another case, a reversible maternal heart failure was noted68 and no complications were observed when administered with vinorelbin69 or alone.70 A severe oligohydramnion, respiratory insufficiency and strong capillary leak syndrome have been reported when a high dose of trastuzumab was administered (56mg/kg total dose).71

Physiological changes during pregnancy may interfere with the pharmacodynamics and pharmacokinetics of chemotherapy. An increase of the glomerular filtration rate can increase the clearance of drugs that are excreted by the kidney. In addition, metabolisation of drugs in the liver is increased and can influence the presence of active drugs. The increase in the plasma volume is likely to reduce plasma levels of cytotoxic drugs, while increased protein binding will also lead to decreased availability of active drugs. Amniotic fluid can act as a third space for some drugs. Despite these changes, prospective pharmacokinetic studies on chemotherapy dosing fail, but are urgently needed. In the absence of valid data, the same dosages and schemes are used as used in non-pregnant women, based on height and weight.

Since haematological toxicity can put the mother as well as the foetus at risk for infections and bleeding complications during delivery, an interval of 3–4 weeks between the last chemotherapy administration and delivery is aimed for. Chemotherapy is therefore not administered after 35 weeks of pregnancy.

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Neonatal and long-term outcome after in utero exposure to chemotherapy 

The administration of cytotoxic agents during the foetal phase, the second and third trimester of pregnancy, will not cause malformations. However, cases of growth restriction, prematurity, haematopoietic suppression, intrauterine and neonatal deaths have been described. Follow-up at a high-risk obstetrical unit is recommended.*1, *4, 72, *73, 74

Although chemotherapy is currently administered during the second and third trimesters of pregnancy, convincing data on long-term outcome are still lacking. The available literature is limited due to the heterogeneity, retrospective nature of studies, short follow-up period and limited evaluation of the children. Moreover, the interpretation of the outcome results is difficult as there are many confounding factors in these cases, such as stress, maternal cancer, often prematurity, etc.

Hahn et al. described 57 patients who were treated for breast cancer during pregnancy.75 The parents/guardian or teachers were questioned regarding the wellbeing of the child by email or phone call. Respiratory problems were the most important neonatal complications (N=10). One child suffered from subarachnoidal bleeding, and three congenital anomalies were registered as well. Medical problems were reported in 57% of children, and included allergy, eczema, asthma and upper respiratory infections. Two out of 18 school-going children needed special attention.

Aviles and Neri described 84 cases of in utero exposure to chemotherapy for haematological malignancies.76 The median follow-up period was 18 years (range: 6–29 years) and the authors concluded that all 84 children, and also 12 children from the second generation, had a normal development. Up till now, one case of a secondary malignancy has been described by Zemlickis et al.77; it concerned a twin pregnancy exposed to cyclophosphamide. One child was born with congenital malformations and developed thyroid cancer at the age of 11 and a neuroblastoma at the age of 14. The twin sister, however, was healthy.

Systematic physical and neuropsychological examination of 10 children with a median age of 35 months showed one child with a serious developmental delay.78 On MRI, unilateral polymicrogyria was found in one of the twin born at 32 weeks. Whether this is related to the exposure to chemotherapy is not known. Otherwise, no developmental problems were encountered. It is important to note here that the neonatal morbidity seen in this group of children appeared to be mainly related to prematurity.

Aviles et al. described no cardiac side effect in the offspring after anthracycline exposure during pregnancy.79 However, a case of foetal death29 and two cases of transient dilated cardiomyomyopathy80, 81 have been described after in utero exposure to idarubicin.82

Apart from immediate effects, pre-term birth has also been demonstrated to be associated with long-term morbidities and impaired cognitive and behavioural outcomes.83

With regard to the timing of delivery, if possible, it should be delayed till 35–37 weeks' gestation. Furthermore, since haematological toxicity can put the mother at risk during delivery, an interval of 3–4 weeks between the last administration of chemotherapy and the delivery should be aimed for.

Thus, available data are, although limited, relatively reassuring and do not show an excessive increased risk for congenital malformations after intrauterine exposure to chemotherapy during the second and third trimesters. Long-term systematic follow-up data are urgently needed to provide more safety data on cognitive and cardiac function, fertility and the occurrence of secondary malignancies or germ cell mutations.

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Organ pathology 

Breast cancer 

With an incidence of 10–30 cases per 100 000 pregnancies, it is among the most frequent malignancies occurring during gestation.84 The average age of patients with breast carcinoma in pregnancy is between 35 and 38 years.85 Several studies matched patients with pregnancy-associated breast cancer (PABC) and patients with non-gestational breast cancer for stage and age.86, 87, 88, 89, 90, 91, 92, *93, 94, 95 Accordingly, an unfavourable prognosis has been attributed to late diagnosis rather than distinct tumour biological behaviour. Few studies have specifically compared subgroups of PABC patients (e.g., those with breast cancer during pregnancy and those with breast cancer diagnosed within 1 year after delivery). Comparing overall survival in patients with PABC, lactating women with breast cancer and matched controls, a worse prognosis in patients with cancer diagnosed during lactation has been observed.*3, 90, 95

Early diagnosis is more difficult due to mammary gland proliferation during pregnancy. Mammography during pregnancy has a high false-negative rate due to higher density of mammary gland. Standard mammography in two projections irradiates the foetus by a maximum of 0.004Gy, making the procedure possible during pregnancy. Similarly to non-pregnant women, ultrasonography with core-cut biopsy is standard.

There is no evidence indicating a better outcome after termination of pregnancy.91 A greater tumour size at diagnosis during pregnancy can necessitate a radical modified mastectomy with axillary lymphadenectomy. Since adjuvant chemotherapy is mostly indicated in young women, radiotherapy can be postponed until after delivery. Breast-conserving surgery during pregnancy is therefore an option when indication criteria are fulfilled.96 Neo-adjuvant chemotherapy can be used during pregnancy. Sentinel node identification during pregnancy is possible and has been discussed earlier.

Pre-invasive cervical cancer 

The incidence of pre-invasive lesion complicating pregnancy varies between 2000 to 8000 per 100 000 pregnancies.97

The interpretation of cytology as well as of colposcopy is more difficult than in non-pregnant state due to increased cervical volume, increased vascularisation, stromal oedema and glandular hyperplasia. The indication for colposcopy is the same as in non-pregnant women. Colposcopy is more difficult although eversion of the cervix facilitates inspection. Most studies report low risks of colposcopy-guided punch biopsies.98 Endocervical curettage is not recommended during pregnancy. Only about 0–10% of biopsy-proven CIN II and CIN III progress towards invasive cancer, whereas regression has been observed in 47–70%.99, *100, 101, 102 Progression into frankly invasive (>stage Ia2) cervical cancer has not been documented. Therefore, a conservative approach during pregnancy is proposed when CIN is diagnosed. Repeat colposcopy every 12 weeks is advocated to monitor the disease. Treatment can be postponed until the postpartum period. Some studies have demonstrated a higher regression rate in case of vaginal delivery103, though this has not been confirmed in the other studies.101

Conisation is rarely indicated during pregnancy. In cases of a suspicion of micro-invasive carcinoma, a flat cone biopsy is indicated. The procedure is preferably performed by needle or LLETZ from 12th till 20th week of pregnancy. Most complications such as premature delivery are associated with the procedure performed during the third trimester.104

Invasive cervical cancer 

The incidence of cervical cancer during pregnancy is estimated to vary approximately 10–50 per 100 000 pregnancies, rendering cervical cancer the second most common malignancy diagnosed during pregnancy. Prognosis seems not to be influenced by pregnancy.*3, 105

Symptoms are absent in stage IA disease106, whereas post-coital bleeding or spotting occur in 20% and abnormal oncological cytology in 63% with stage I cancer during pregnancy.107 MRI identifies invasion into vagina, parametria and pelvic lymph nodes108, 109 and can be used during pregnancy.

The treatment is dependent on the wish of the patient to preserve the pregnancy, stage of the disease and gestational age. Although treatment for cervical cancer is possible, safety data are limited and the experimental nature should be explained.

When preservation of the pregnancy is not the aim, standard treatment is used. Radiation during pregnancy is possible. When applied with foetus in utero it leads to spontaneous abortion, usually within 24–34 days.110, 111 Some authors advocate a hysterotomy to remove the foetus111, 112, but complications such as pyometra might occur.113 Delay in initiating radiation treatment should be limited to 4 weeks.114, 115

When cancer is diagnosed during the first trimester and if pregnancy preservation is aimed for, treatment could be postponed until the second trimester. From the second trimester onwards, surgery and chemotherapy can be used in selected cases. When diagnosed during the third trimester, therapy after the delivery is advisable.

Historically, when cervical cancer was diagnosed after 20 weeks, delay for cancer treatment has been proposed (up to 32 weeks of delay!) without apparent significant impact on the prognosis. The number of cases is very limited, as summarised by Hunter et al.116 Close observation and serial MRI imaging should be encouraged in these cases.

Successful alternatives to an expectant management have been described. The use of these alternatives is probably a better guarantee that maternal prognosis is prevailed upon when compared to an expectant follow-up. Alternatives include surgery and chemotherapy or a combination thereof.

Surgical treatment 

Early cervical cancer can be treated during pregnancy with surgery alone. Treatment strategy will vary according to the disease stage and surgical skills. Cone biopsy for stage Ia1 cervical cancer is sufficient and has been described. Cone biopsy in combination with pelvic lymphadenectomy during pregnancy, followed by trachelectomy in IA2 cervical cancer after the delivery, has been reported.117 Resection of the cervix with retroperitoneal lymphadenectomy during pregnancy for stage Ib1 cervical cancer is possible in selected cases with superficial growth.118

Radical vaginal trachelectomy in the 16th week of pregnancy119 and radical abdominal trachelectomy during the first and second trimesters120 have been described with 40% success of delivering a healthy child. However, surgical experience is crucial, and the blood loss is high.

When the pregnancy is more advanced, caesarean section followed by radical hysterectomy has been reported in few papers. Blood loss (800–1200ml) and postoperative complications including pulmonary embolism and vesicovaginal fistula121, 122, 123, 124 should be taken into account. This surgical treatment option should only be offered in specialised teams. Deferring the final surgery by 2–6 weeks after a caesarean section appears to be a valuable alternative.

Chemotherapy 

Neo-adjuvant chemotherapy is an option to stabilise the disease and to reduce the size of the tumour, thus facilitating a better operability of the disease. It is also a tool to reach foetal maturity and to surgically treat cervical cancer after – operative – delivery.

Neo-adjuvant chemotherapy with fertility-preserving surgery in non-pregnant women has been reported.125, 126 Nine cases of neo-adjuvant chemotherapy during pregnancy have been found in the literature31, 43, 127, 128, 129, 130, 131, 132 for stages IB1–IIIB. Two maternal deaths were treatment related (abdominal wound metastasis and refusal of treatment). Chemotherapy was in each case platin based.

Pregnancy-sparing treatment by the stage 

For stage IA1 squamous cell carcinoma, cone biopsy with preservation of the foetus can be safely performed ideally between 14th and 20th week of pregnancy.

In stage IA2 and IB1 (smaller than 2cm), a pelvic lymphadenectomy with cone biopsy or simple trachelectomy can be considered. Radical abdominal and vaginal trachelectomy is an option for specialised teams. To stabilise the disease, an administration of neo-adjuvant chemotherapy followed by lymphadenectomy is also possible.

For IB1 (larger than 2cm), IB2 and IIA, a choice between lymphadenectomy and administration of neo-adjuvant chemotherapy, followed by lymphadenectomy, is to be made.

For IIB disease, neo-adjuvant chemotherapy until surgical delivery can be proposed.

Since fatal recurrences in the episiotomy site after vaginal delivery have been reported, a caesarean section is advocated when cervical cancer is still in situ.100

Vulvar cancers 

Vulva carcinogenesis in women under the age of 50 is frequently multifocal and is associated with human papillomavirus infection.133 Approximately 26% of vulvar intra-epithelial neoplasia (VIN) and 19% of invasive vulvar cancer occur in women younger than 40 years.134 The same treatment modalities for VIN as used in the non-pregnant patient, including laser vaporisation, laser skinning or surgical excision, are possible. Although the safe use of imiquimod during pregnancy has been described in a single case135, the application of podophylline and imiquimod remains contraindicated.

Invasive (>1mm) vulvar cancer during pregnancy is uncommon. There are about 32 cases reported up to now.136, 137 In contrast to cervical cancer, there are no data on alternatives to standard treatment during pregnancy, including delay of treatment. Standard treatment should therefore be executed. Bakour et al. summarise 27 cases and state that definitive surgical treatment is recommended before 36 weeks of pregnancy.138 Haemostasis is more difficult during pregnancy due to increased vascularisation. Postoperative follow-up is necessary since recurrence during pregnancy has been described.139 Apart from important postoperative scarring vulvar tissue, caesarean section is only indicated for obstetrical indications.

Endometrial cancer 

We define endometrial cancer related to pregnancy as any endometrial cancer diagnosed during pregnancy or during the puerperium (defined as the period 6 weeks after delivery). Using our definition, 28 published cases are available.140, 141, 142, 143, 144, 145 Diagnosis was made during curettage (n=17, 61%), second to third trimester and at birth (n=8, 28%) or during the puerperium (n=3, 11%). Distribution of pathological type and grading was as follows (n, %): grade 1 endometrioid (21, 75%), grade 2-3 endometrioid (6, 21%) or serous (1, 4%). In all but one case, the uterus was empty when the diagnosis was made.146 In the absence of a foetus, standard treatment for endometrial cancer should be offered. A summary of fertility-sparing treatment options is beyond the scope of this article.

Adnexal masses 

The incidence of adnexal masses during pregnancy varied between 2.3% and 4.1% in two large studies, including 18 391 and 7996 patients, respectively.147, 148 Approximately 90% of these lesions diagnosed during the first trimester of pregnancy will disappear spontaneously. In the remaining 10%, the risk of complications, including rupture, torsion and bleeding, as well as the risk of malignancy, needs to be considered.

Pathologic lesions are most frequently benign and include teratoma, cystadenoma, endometrioma, ovarian cysts or leiomyomas. It is estimated that approximately 6% of all operated adnexal masses are malignant148, including epithelial (49–75%), sex cord stromal (9–16%) and germ cell tumours (6–40%).148, 149 These constitute 3–6% of cancer cases during pregnancy.

The diagnosis and characterisation of the tumours are mainly based on sonar findings because serum alpha-feto-protein, CA 125, human chorion gonadotrophin and inhibin fluctuate during pregnancy and are less specific.148 An expert sonographer needs to be consulted to characterise the lesion. Nulliparity and infertility have been found to be factors of suspicion.150, 151 Malignant tumours are more likely to present at an early stage, due to frequent obstetrical examinations in asymptomatic patients.152 Ultrasound-guided aspiration of the cyst should be used carefully as the sensitivity of diagnosis from aspiration is only 70%153 and the recurrence rate of cyst is about one-third.154 Moreover, the negative influence of leakage on the prognosis was well documented.155

The clinical presentation (pain, abdominal discomfort, etc.) in combination with the sonographic findings of the ovarian mass will guide the decision on surgery during pregnancy. Surgical intervention is indicated for persistent adnexal masses with an unsure biological behaviour. The clinician needs balance between operating too early (risk for miscarriage and adnexectomy with loss of luteal function) and late surgery (complications of benign masses, higher-stage ovarian cancer, premature labour). Postponing surgery increases the risk of torsion (3–15%), rupture (9–17%) and bleeding, which are indications for urgent surgery during pregnancy.148, 149 Emergency surgery during pregnancy is best avoided to enable patient information (risk for premature delivery, strategy in case of unexpected perioperative findings) and an experienced surgeon to be present.

A midline laparotomy with minimal uterine manipulation during the second trimester is preferred. An open laparoscopic procedure is only allowed in the absence of malignant signs and in experienced hands that minimise the risk for spilling, ideally between 16th and 20th week of pregnancy.25, 26

Ovarian cancer 

The incidence of ovarian cancer diagnosed during pregnancy varies about four to eight in 100 000 pregnancies.149, 156

The diagnosis is usually established by routine prenatal ultrasound examination contributing to the early stages. A surgical intervention is needed for symptoms such as torsion, acute abdomen, rupture, bleeding or concern about malignancy.

Borderline tumours as well as non-epithelial neoplasms (germ cell, sex-cord stromal tumours) are usually diagnosed in stage I. They can be treated by midline laparotomy with unilateral salpingo-oophorectomy, omentectomy, peritoneal cytology and blind biopsies during pregnancy. In borderline tumours in selected cases, a laparoscopic procedure can be performed. For higher stages, removal of the adnexa during pregnancy is aimed for with completion of the surgery after delivery.

For invasive epithelial ovarian carcinoma, the treatment depends on the stage and grade. For stage IA, grade 1 surgical staging is similar to borderline tumours. Post-delivery re-staging may be considered since staging – especially the pelvis – during pregnancy is not satisfactory. For stage IA grade II–III, IB, IC and IIA, lymphadenectomy and adjuvant platin-based chemotherapy are mandatory. If the patient is upstaged, paclitaxel- and platinum-based chemotherapy during pregnancy and final surgery after delivery are needed.

In advanced-stage ovarian cancer during pregnancy, different treatment strategies have been described, including primary debulking with termination of pregnancy40, 157 or delivery*158, 159 expectant management40, 160, surgery during pregnancy followed by postpartal chemotherapy40, 160, surgery (including cytoreductive surgery) followed by chemotherapy during pregnancy with final surgery during/after delivery.33, 46, 47, 48, 54, 55, 56, 160, 161, 162, 163 If final surgery in the postpartum period is needed, surgical intervention during pregnancy should best be as minimal as possible to avoid jeopardising foetal chances.

Paclitaxel–carboplatin chemotherapy until foetal maturity is the regimen of choice. Vaginal delivery, followed by final surgery in the postpartum period or planned laparotomy for caesarean section and (interval)-debulking may be considered.

In summary, when cancer complicates pregnancy, a multidisciplinary approach and extensive information of the parents are necessary. Termination of pregnancy is unlikely to improve maternal outcome. Staging examinations are possible but should take the pregnant condition into consideration and be as similar as possible to the non-pregnant woman. Surgery and chemotherapy are possible as well, especially after the first trimester. Radiotherapy of the upper abdomen is possible during the first and second trimesters. In order to preserve maternal chances, the treatment strategy should follow standard cancer treatment as close as possible. Administration of chemotherapy after the first trimester does not increase the incidence of congenital malformations. To prevent neonatal and long-term cognitive problems induced by prematurity, continuation of pregnancy until full term is advocated.

Practice points

 


•the incidence of cancer during pregnancy is likely to increase

•a multidisciplinary approach is mandatory

•termination of pregnancy does not improve the maternal outcome

•chemotherapy during the first trimester results in increased rates of congenital malformations but can be administered from the second trimester on

•radiotherapy of the upper part of the body is possible during pregnancy and the distance to the foetus determines the risk

•abdominopelvic surgery including laparoscopy is safe in experienced hands

•the same dosages of chemotherapy should be used as in non-pregnant women

•delay of treatment or undertreatment is a major maternal risk factor

•prematurity and its long-term cognitive effect is a major foetal risk factor

Research agenda

 


•data on the transplacental transport of cytotoxic drugs

•impact of the physiological changes during pregnancy on the pharmacokinetics of cytotoxic drugs

•more studies are needed to document the long-term outcome of the offspring after cancer treatment during pregnancy

Back to Article Outline

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☆ Frédéric Amant is clinical researcher for F.W.O.; Kristel Van Calsteren is aspirant for F.W.O.; This work is supported by F.W.O. Project G. 0358.06, ‘Stichting tegen kanker Project SCIE2006-17’, Research Fund K.U.Leuven.

PII: S1521-6934(09)00102-3

doi:10.1016/j.bpobgyn.2009.08.001

Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 61-79, February 2010

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