Malaika Amneus and Christine H. Holschneider
The diagnosis of cancer complicates approximately 1 in 1000 pregnancies. Once diagnosed, emotional, ethical, diagnostic, and treatment dilemmas confront both the patient and the treating physicians, posing unique challenges. Questions regarding whether or not to terminate the pregnancy, potential maternal risk of delays in cancer treatment, fetal risks of early delivery, and maternal and fetal effects of cancer treatments during gestation are complex and competing factors that make decision making both medically and emotionally challenging. Limited data on the treatment of malignancies during pregnancy and absence of randomized controlled studies in this population contribute to the lack of generalized treatment algorithms. Individualization of treatment planning with a multidisciplinary team is essential. Considerations not only include the risk/benefit assessment of treatment modalities such as chemotherapy, radiation therapy, and surgery during pregnancy, but also include the potential maternal and fetal consequences of diagnostic procedures.
The most common malignancies during pregnancy include those that are most commonly found in women of reproductive age and include cervical and ovarian cancer. The most common nongynecologic malignancies are breast cancer, malignant melanoma, thyroid cancer, and hematologic malignancies.1-3 Given that the incidence of malignancies increases with increasing age, as more women choose to delay childbearing, it is expected that the incidence of cancer during pregnancy will increase.
RADIATION IN PREGNANCY
Key Points
1. The developmental effects of radiation exposure on pregnancy is related both to the dose of radiation as well as the gestational age.
2. Computed tomography and magnetic resonance imaging, including scans of the pelvis, are associated with negligible fetal risk.
Ionizing radiation is used routinely during imaging for cancer staging or disease surveillance, and radiation therapy is a common component of the treatment of many cancers in the nonpregnant patient. In pregnancy, consideration has to be given not only to the radiation exposure of the mother, but also that of the developing fetus. Much of what we know about the effects of radiation on pregnancy is based on animal studies, accidental or incidental human exposures to diagnostic and therapeutic radiation, and data gathered from victims of radiation exposure after the atomic bombings of Hiroshima and Nagasaki. There are many confounding factors that limit our interpretation of these data, including species differences, potential differential effects of various types of ionizing radiation, lack of certainty regarding the doses of radiation received, potential differential effects of single versus multiple exposures, and the baseline rate of human malformations and other negative outcomes. Given the lack of controlled studies on the issue, patient counseling regarding radiation exposure in pregnancy may be challenging, even as it relates to imaging procedures. The growing importance of this issue is evidenced by a recent review that noted a 107% increase over the past decade in the use of imaging studies using ionizing radiation during pregnancy.4
The developmental effects of radiation exposure on a pregnancy are related not only to the dose of radiation, but also to the gestational age of the pregnancy. Gestation can be generally divided into 3 periods: preimplantation (0-2 weeks after conception), organogenesis (2-8 weeks after conception), and the fetal period (> 8 weeks after conception). Radiation exposure has different potential developmental effects during each of these periods (Table 16-1).5,6 In addition, radiation exposure can lead to genetic cell injury and an increased malignancy risk at any gestational age.
Table 16-1 Developmental Effects of Ionizing Radiation at Different Gestational Ages7,8
During the preimplantation period, radiation exposure is thought to have an “all or none” effect; that is, the embryo dies, or there is no consequence.7 This may be explained by the fact that at this early stage of development, the embryo is composed of totipotent cells. If the radiation causes the death of a sufficient number of these cells, the embryo will not survive. Otherwise, the remaining cells will continue to divide and the insult will be overcome without further sequelae. Exposure to 10 cGy (10 rads) or more is generally thought to result in pregnancy loss during the preimplantation period.8
During the period of organogenesis, the fetus is most susceptible to the teratogenic effects of radiation exposure. Notable effects include microcephaly, microphthalmia, eye anomalies, mental retardation, genital malformations, and growth restriction.6,9 It is the current consensus that exposure to < 5 cGy (< 5 rads) of radiation is not related to an increased risk of fetal malformation,8 and it is important to note that no single common diagnostic imaging procedure in use today results in exposures at this level (Table 16-2). However, such levels can be quickly reached with multiple imaging studies, therapeutic radiation, and fluoroscopic procedures. Although concerns about exposure in the range of 5 to 10 cGy (5-10 rads) have been raised, significantly increased developmental risk to the embryo and fetus is not known until the absorbed dose reaches at least 10 cGy (10 rads).
Table 16-2 Estimated Fetal Radiation Exposure From Common Diagnostic Radiologic Procedures10,11
During the fetal period, the effects of radiation exposure seem to be limited to growth retardation, microcephaly, and central nervous system (CNS) defects (decreased IQ and mental retardation).5,6 The period from the 8th to 15th weeks appears to be the period of greatest vulnerability of the CNS, and it is estimated that the probability of mental retardation is approximately 40% for every 100 cGy (100 rads) exposure above 10 cGy (10 rads).12 The sensitivity of the CNS to radiation is less during the 16th to 25th weeks, and studies have estimated a 13- to 21-point reduction in IQ for every 100 cGy (100 rads) of radiation exposure above 10 cGy (10 rads).5 The radiation sensitivity of the CNS is even further reduced after 25 weeks.
In addition to the potential developmental effects of radiation exposure, there is also concern for an increased risk of childhood cancers (both leukemias as well as solid tumors) in children exposed to radiation in utero. The relative risk for childhood cancer associated with in utero radiation exposure, as found in the large Oxford Survey of Childhood Cancers as well as in a 1993 meta-analysis, is approximately 1.4.13 The excess childhood cancer risk attributable to in utero radiation exposure is estimated to be 6% per 100 cGy, with an increase in risk starting to become appreciable at doses as low as 1 cGy.13 Although it may sound alarming that a standard pelvic CT scan may potentially double the risk of fatal childhood cancer, this must be viewed in context of the low baseline risk (approximately 1 in 2000)9 and the potential benefit to the management of mother and pregnancy of the information gained by the imaging study. One significant difficulty in interpreting this literature is due to the fact that much of the data stem from case-control studies collected over many decades, during and after which radiation exposure with diagnostic imaging has been greatly reduced. In fact, recent population-based data from Ontario using 1.8 million maternal-child pairs from 1991 to 2008 found no increase in childhood cancers in the offspring of 5590 mothers exposed to major radiodiagnostic testing in pregnancy (crude hazard ratio of 0.69; 95% confidence interval, 0.26-1.82).14
Computed Tomography in Pregnancy
It is generally agreed that imaging modalities that do not involve ionizing radiation, such as ultrasound and magnetic resonance imaging (MRI), are preferred in pregnancy as long as they adequately provide the desired diagnostic information. However, as demonstrated in Table 16-1, the radiation dose to the fetus from a computed tomography (CT) scan, even of the pelvis, is below a dose expected to be associated with considerable fetal risk. It is thus unacceptable to delay diagnostic work-up of a pregnant patient with suspected cancer if the information gained from the imaging study is expected to affect management. In addition, such exposure per se should not alter the management of the pregnancy. Despite this, a survey of physicians published in 2004 indicated that up to 6% would recommend pregnancy termination after an abdominal CT scan in early pregnancy,15 highlighting the need for provider education. In addition to the potential effects of exposure to ionizing radiation during a CT scan discussed previously, there may also be concerns about the safety of intravenous (IV) contrast administration during pregnancy. Iodinated contrast media do not appear to be teratogenic in animals. Human data are lacking, and thus they are considered US Food and Drug Administration (FDA) category B drugs. The use of iodinated contrast agents is considered acceptable in human pregnancy when it is necessary for appropriate diagnosis and after informed consent.16 There is a theoretical risk of depression of neonatal thyroid function with in utero exposure to iodinated agents. However, there are no clear data that demonstrate any considerable increased risk associated with contrast exposure for CT scan during pregnancy. The thyroid function of neonates is routinely assessed in the United States, regardless of any in utero exposure to iodinated agents.
Magnetic Resonance Imaging in Pregnancy
MRI during pregnancy has been used for both maternal and fetal indications, and there is no evidence that human fetal exposure to MRI with 1.5 Tesla magnets has resulted in any negative fetal effects. The 2007 American College of Radiology Guidance Document for Safe MR Practices states that it is acceptable to perform magnetic resonance scans at any time point during pregnancy when the radiologist and referring physician believe that the risk-benefit ratio warrants performance of the study.17 Some theoretical concerns involve potential teratogenicity and acoustic damage. However, thus far, studies have failed to substantiate these concerns. A study of 35 children who were exposed to 1.5-Tesla MRI during the third trimester of pregnancy found no harmful effects attributable to MRI, in particular no negative effects on vision or hearing.18 Normal pediatric assessment and developmental outcomes were found in a study of 20 9-month-old infants who were exposed in utero to 4 series of echoplanar imaging MRI between 20 weeks and term.19
The use of gadolinium-based contrast is controversial. Animal studies have shown potential teratogenic effects at high doses.6 Studies show that the contrast agents cross the placenta, are filtered by fetal kidneys, and appear in fetal urine. Because they are excreted into the amniotic fluid, there are concerns regarding potential long-term exposure of the fetus due to recirculation and delayed elimination. The American College of Radiology recommends that before administration of gadolinium-based contrast agents in pregnancy, “a well-documented and thoughtful risk-benefit analysis…” be performed that substantiates an “overwhelming potential benefit to the patient or fetus…”,.17However, the US FDA classifies gadolinium as a class C drug, and the European Society of Radiology states that based on available evidence, the use of gadolinium in pregnancy appears to be safe.20 Thus, even though current radiology practices and recommendations in the United States discourage the use of gadolinium-based contrast agents during pregnancy because their safety for the fetus has not yet been proven, gadolinium use should be considered when the diagnostic study is important for the health of the mother.
Therapeutic Radiation in Pregnancy
Although the dose of fetal radiation for most diagnostic procedures is low, administration of therapeutic radiation during pregnancy can result in significant fetal doses. Therapeutic radiation to sites remote from the uterus may be indicated during pregnancy for some cancers and can be administered to a well-informed patient. The dose of radiation administered to the fetus depends on several factors, including the target dose of radiation, the size of the radiation field, the type of teletherapy machine used, the distance of the fetus from the edge of the radiation field, and the use of wedges, blocks, and other objects that cause scatter.21 In addition to the scatter from the teletherapy machine and from beam modifiers, internal scatter within the patient also affects the dose received by the fetus. The use of proper shielding of the uterus can reduce the fetal dose by up to a factor of 4.22,23 Cobalt-60 irradiation is associated with a higher fetal dose compared with high-energy photons. Additionally, the use of high-energy photon beams > 10 MV produce a photoneutron contribution to the radiation dose, and it is generally recommended that photons < 10 MV be used whenever possible.
Woo et al24 reported on 16 patients with Hodgkin lymphoma who were treated with radiation during pregnancy. Eleven patients received mantle radiation, 3 received radiation to the neck and mediastinum, and in 2 patients, radiation was limited to the neck. The dose to the mid-fetus was estimated in 9 cases and ranged from 1.4 to 5.5 cGy with 6-MV photons and from 10 to 13.6 cGy for cobalt-60. All patients went on to delivery healthy infants. Antypas et al25performed in vivo as well as phantom measurements of the fetal dose of radiation in a patient irradiated for breast cancer from the second to sixth week of gestation. There was no shielding used. The total tumor dose was 46 Gy, and the fetal dose was estimated at 3.9 cGy. The importance of gestational age and uterine size for the fetal dose of radiation is exemplified when these measurements are compared with those obtained by Ngu et al26; breast irradiation to 50 Gy in late pregnancy resulted in an estimated 21-cGy unshielded dose, which reduced to 14 to 18 cGy with shielding.
If a patient presents with an unplanned pregnancy during radiation therapy for cancer, the risk of poor fetal outcome after fetal radiation exposure is dependent on the fetal dose received. The radiation oncologist and physicist involved in the patient’s radiotherapy should be asked to estimate fetal radiation exposure. The results of such evaluation should be discussed with the patient and her family to allow her to make an informed decision regarding her pregnancy in the context of her underlying disease and other concurrent therapy received or planned.
CHEMOTHERAPY IN PREGNANCY
Key Points
1. Chemotherapy exposure in the first trimester is associated with a 20% incidence of fetal malformations, which exceeds the 3% to 4% rate of fetal malformations in the general population.
2. In the second and third trimester, the most significant potential negative effects of chemotherapy during pregnancy are growth restriction and pre-term birth.
To patients, the prospect of undergoing chemotherapy is often accompanied by apprehension and fear, both in relation to the anticipated physical and emotional effects of treatment, as well as in regard to whether or not the treatment will be effective. When a pregnant patient faces chemotherapy, these concerns are compounded by concerns about the effect of the treatment on the pregnancy and the developing fetus. Several factors, including the chemotherapeutic agent, placental transfer, timing of treatment, dose, and frequency of exposure, influence the effects of chemotherapy on the fetus. Again, there is a lack of controlled data in humans, and thus our knowledge of the effects of chemotherapy during pregnancy are limited to animal studies and human case series and case reports. Depending on the type of malignancy, the stage of disease, and the gestational age of the pregnancy, there are times when appropriate therapy can be delayed until after delivery, or other modalities of treatment, such as surgery, can be used during the pregnancy with adjuvant therapy delayed until after delivery. However, when chemotherapy is likely to improve maternal outcome, it can be administered during pregnancy to an appropriately informed patient.
The concepts regarding the importance of gestational age on the effects of chemotherapy on a developing pregnancy are similar to those in radiation. Chemotherapy within the first 2 weeks after conception appears to have an “all or none” effect, resulting in either spontaneous abortion or no effect. The most sensitive time for potential teratogenesis is during organogenesis. The organs that continue to develop throughout gestation, such as the nervous system, eyes, and bone marrow, remain at risk even after this window. In general, chemotherapy exposure in the first trimester is associated with a 20% incidence of fetal malformations, which exceeds the 3% to 4% rate of fetal malformations in the general population.
In the second and third trimester, the most significant potential negative effects of chemotherapy during pregnancy are growth restriction and preterm birth. A review of published cases of in utero exposure to chemotherapy identified a less than 4% incidence of malformations, a 7% incidence of intrauterine growth restriction, and a 5% incidence of spontaneous preterm delivery. Of the 11 cases of malformation, 9 were associated with first trimester exposure.27 The most recent large report comes from the Cancer and Pregnancy Registry and includes data from 231 women diagnosed with a variety of cancers during pregnancy who were voluntarily reported to the registry. Of these patients, 13 terminated their pregnancy and 157 received chemotherapy during pregnancy. Of the infants exposed to chemotherapy in utero, 3.8% had a malformation. Fewer than 8% of infants had a birthweight less than the 10th percentile, and 6% spontaneously delivered prematurely (iatrogenic preterm delivery excluded).28 The rates of malformation, intrauterine growth restriction and spontaneous preterm delivery in these studies do not exceed those seen in the general population. Although these data are encouraging and can be used for the counseling of patients, some uncertainty continues as a result of the lack of long-term follow-up. The incidence of clear cell carcinoma of the cervix and vagina in women exposed to diethylstilbestrol in utero is a reminder of the importance of continued long-term follow-up.
Although the timing of delivery is not always predictable for obstetrical reasons, it is generally recommended to avoid delivery during the peak of the hematologic toxicity of chemotherapy treatment in the mother. An additional consideration is the potential for neonatal myelosuppression. For example, in a study on the treatment of leukemia during pregnancy, one-third of the infants exposed to chemotherapy within 1 month before delivery were cytopenic at birth.29 Due to this potential complication and the resultant potential risk for neonatal sepsis or bleeding, it is typically recommended that administration of chemotherapy be avoided within 3 weeks of anticipated delivery. This also allows for fetal drug excretion via the placenta, as drug metabolism in the neonate may be impaired, leading to potential increased toxicity.
In addition to the concerns regarding potential consequences of chemotherapy exposure for the fetus, careful consideration must be given to the physiologic changes that accompany the pregnant state and how those may affect the dosing and toxicity of chemotherapy. Such physiologic changes include an increased plasma volume, an increased glomerular filtration rate, decreased serum albumin, delayed gastric emptying and reduced intestinal motility, alterations in hepatic metabolism, and the creation of a physiologic third space (amniotic fluid). These changes may significantly affect the pharmacokinetics of drugs due to increased volume of distribution, altered protein binding, increased renal clearance, altered drug absorption, enterohepatic circulation, and hepatic clearance, with subsequent effects on peak drug concentration, drug half-life, and area under the curve (Table 16-3). Due to the paucity of data, chemotherapy during pregnancy is usually administered without dose modification compared with non-pregnant patients. Toxicities, response to treatment, and fetal well-being must be carefully followed throughout treatment and adjustments to treatment regimens and supportive care made when clinically indicated.
Table 16-3 Pharmacokinetic Consideration Regarding Chemotherapeutic Drugs in Pregnancy30,31
Chemotherapeutic Agents in Pregnancy
Information regarding the use of specific chemo-therapeutic agents during pregnancy is limited largely to case reports, small case series, and some registry reports of single-agent or combination therapy use. In addition to the FDA classification of drugs in pregnancy (Table 16-4), several resources can provide information to guide clinicians in the administration of chemotherapy in this setting. These include textbooks such as Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (Briggs, Freeman, and Yaffe, now in the 9th edition), as well as internet-based resources such as Reprotox (www.reprotox.org), TERIS (depts.washington.edu/terisweb), and the Cancer and Pregnancy Registry (www.cooperhealth.org/content/pregnancyandcancer.htm).
Table 16-4 United States Food and Drug Administration (FDA) Classification of Fetal Risks due to Pharmaceuticals36
Antimetabolites
Antimetabolites, especially folic acid antagonists, are the agents most commonly associated with fetal malformations. First-trimester exposure to aminopterin is associated with a series of abnormalities that includes cranial dysostosis, hypertelorism, abnormalities of the external ear, and micrognathia, as well as potential limb deformities and neurologic abnormalities. Methotrexate exposure in the first trimester has resulted in similar anomalies, and methotrexate is considered one of the most teratogenic medications and is classified as a class X drug by the FDA. These findings have been termed aminopterin-methotrexate syndrome. Of 6 first-trimester exposures to cytarabine (alone or in combination with other chemotherapeutic agents), there were 2 congenital abnormalities.32 Mercaptopurine appears to be associated with a low rate of congenital malformations, with 1 abnormality noted of 34 cases of first-trimester exposure.33 A recent series of breast cancer patients treated with chemotherapy during pregnancy included 9 patients who received combination therapy with cyclophosphamide, methotrexate, and fluorouracil (none in the first trimester), with no adverse outcomes noted.34
Alkylating Agents
A review of use of alkylating agents during pregnancy found a 14% incidence of malformation with administration in the first trimester, but when treatment was limited to the second and third trimester, the rate of malformations was not above that of the general population.35 Reported malformations after administration of cyclophosphamide during the first trimester of pregnancy have included absent or hypoplastic digits, eye abnormalities, cleft palate, flat nasal bridge, and many other abnormalities.27,33 An interesting case report involves a diamniotic-dichorionic twin pregnancy treated with cyclophosphamide throughout pregnancy for acute lymphocytic leukemia. One twin (female) was without abnormalities, whereas the other (male) had multiple abnormalities including but not limited to esophageal atresia, an upper extremity deformity, and a renal abnormality. He also went on to develop thyroid cancer at 11 years of age and neuroblastoma at 14 years of age.37 Chlorambucil administration during the first trimester is associated with renal agenesis in both animals and humans.33 Dacarbazine is used in the treatment of Hodgkin lymphoma and has been administered during pregnancy as part of the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen. In one review, no malformations were noted in 15 pregnancies (some included first-trimester use).38
Antibiotics
Anthracyclines incompletely cross the placenta, and their use in pregnancy has not been associated with an increase in fetal malformations. A recent review of the literature analyzed outcomes in 160 pregnancies exposed to anthracyclines (90% in combination regimens). This included 31 patients exposed in the first trimester. They noted a malformation in 3% and fetal death in 9%. Eighty percent of the malformations were associated with first-trimester exposure. Fetal death was in conjunction with maternal death in 40% of the cases. Of the fetal deaths, 87% were in patients with acute leukemia, and 73% were associated with daunorubicin exposure, leading many to now avoid this agent in pregnancy in favor of doxorubicin.39 An additional concern with the use of anthracyclines in pregnancy is the potential for cardiac toxicity in children exposed to the agents in utero. A recent report with long-term outcomes (mean, 17 years) of cardiac function of such children was encouraging, finding no evidence of late cardiac toxicity.40 Bleomycin use in pregnancy is somewhat more controversial. At least 9 cases of bleomycin, etoposide, and cisplatin (BEP) use in pregnancy have been reported; in 2 of those poor neonatal outcomes that were noted, 1 included ventriculomegaly and cerebral atrophy.41
Vinca Alkaloids
Vinca alkaloids are embryocidal and teratogenic in animal studies, and scattered reports suggest potential malformations after administration of these drugs.30,33,38 However, several case reports also suggest the relative safety of these agents in human pregnancy.30 For example, in a review of 6 cases of vinorelbine exposure during pregnancy (none in the first trimester), there were no malformations noted, and short-term outcomes of the infants were positive.42The use of vinblastine and vincristine (including during the first trimester) has also been reported, and there is no clear evidence of an increased risk of fetal malformations.33
Platinum Agents
Although platinums are the most commonly used chemotherapeutic agents in pregnancy, data regarding the use of these agents during pregnancy is still limited. There are several case reports on the use of cisplatin or carboplatin alone or in combination with other agents after the first trimester without resultant congenital abnormalities.10,43-46 A recent review by Mir et al47 identified 43 patients in the literature who had been treated with cisplatin (36 patients), carboplatin (6 patients), or both (1 patient), with more than 80% of the cases receiving combination therapy. In the 36 cases of cisplatin exposure, they noted 3 cases of intrauterine growth restriction (IUGR), 2 cases of oligohydramnios, 1 case of polyhydramnios, 1 case of microphthalmos, and 1 case of ventriculomegaly. The association of these malformations with cisplatin remains speculative due to concomitant exposure to other potentially teratogenic drugs. Unremarkable neonatal examination and pediatric development were reported in 34 of 36 children after in utero exposure to cisplatin. In the small number of carboplatin exposure cases described, there were no noted malformations or fetal toxicities noted. A recent study of 7 women who received cisplatin monotherapy for cervical cancer in the second and third trimester of pregnancy reports the concentration of cisplatin in the maternal blood, umbilical cord blood, and amniotic fluid measured at the time of delivery. Maternal serum cisplatin concentrations ranged widely, depending on the number of prior cycles and time interval to last treatment. Amniotic fluid cisplatin concentrations were 13% to 42% and umbilical artery levels 31% to 65% of the maternal serum concentration. Eight healthy infants were born with no anomalies and normal short-term development.48
Taxanes
The large molecular weight and high degree of protein binding of paclitaxel likely limit transfer of the drug across the placenta.33 Human data remain very limited. There are case reports of paclitaxel administration along with a platinum agent for the treatment of ovarian cancer during pregnancy10,49 without evidence of fetal malformation or developmental abnormalities. Additional cases of taxane administration during pregnancy are reported through the Cancer and Pregnancy Registry28 without fetal malformations.
Topoisomerase Inhibitors
Data regarding the use of etoposide, topotecan, and irinotecan during pregnancy are scant to nonexistent. Use of etoposide has been reported during the second and third trimester, and pancytopenia and IUGR have been noted,50,51but there are no reports of fetal malformations.
Supportive Medications
Recombinant erythropoietin does not appear to cross the placenta and does not seem to pose a risk to the fetus. Given the increased risk of thromboembolic disease associated with the use of recombinant erythropoietin and darbepoetin in cancer patients52 and the already increased risk of thromboembolic disease associated with pregnancy,53 caution may be warranted.
Granulocyte colony-stimulating factor administration is not teratogenic in animals.33 It does cross the placenta,54 but administration during pregnancy appears to be safe. For example, a study from the Severe Chronic Neutropenia International Registry included 20 pregnancies exposed to treatment, with no adverse outcomes noted.55
The antiemetics metoclopramide and ondansetron are pregnancy class B and considered safe in pregnancy. Although malformations have been described in children exposed to prochlorperazine in utero, a large study including 2023 total exposures and 877 exposures during the first trimester found no increase in malformations and no other negative impact.56
Large studies have noted an association between the use of systemic corticosteroids in the first trimester and orofacial clefts. For example, a case-control study noted an odds ratio (OR) of 4.3 for isolated cleft lip with or without cleft palate and an OR of 5.3 for isolated cleft palate with first trimester exposure.57
The antihistamines ranitidine, cimetidine, and diphenhydramine are all class B agents and are considered safe in pregnancy. Due to concerns about antiandrogenic activity of cimetidine, some recommend that ranitidine is preferred over cimetidine.58
For pain control, acetaminophen is the first-line choice for mild pain and is not teratogenic. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased rate of spontaneous abortion with first trimester use. Additionally, in the third trimester, NSAIDs have been linked to decreased amniotic fluid volume and constriction of the ductus arteriosus.59 Additionally, a large nested case-control study with more than 36,000 pregnant women noted that the OR for congenital anomalies for women who filled prescriptions for NSAIDs during the first trimester was 2.21 (95% confidence interval [CI], 1.72-2.85) and for anomalies related to cardiac septal closure the OR was 3.34 (95% CI, 1.87-5.98).60 Opioids are not teratogenic, but do cross the placenta and pose the risk of fetal or neonatal withdrawal. Acute opioid withdrawal should be avoided during pregnancy, as it can be life-threatening to the fetus. Infants born to mothers who chronically take opioids should be carefully monitored for neonatal abstinence syndrome, characterized by apnea, autonomic dysfunction, diarrhea, diaphoresis, lacrimation, irritability, respiratory distress, seizures, tachypnea, and wakefulness, and treated with careful weaning of opioids.
CERVICAL CANCER
Key Points
1. The mechanisms to diagnose cervical cancer during pregnancy are the same as those used in nonpregnant patients and include cytology, colposcopy, cervical biopsy, and, in carefully selected cases, cervical conization.
2. There is a high rate of postpartum regression of abnormal cervical cytology and cervical dysplasia diagnosed in pregnancy.
3. Management of invasive cervical cancer diagnosed in pregnancy must include consideration of gestational age, fetal viability, disease stage, and patient preferences regarding pregnancy and treatment.
Epidemiology
The incidence of cervical cancer in pregnancy varies from 0.12 to 1.06 per 1000 pregnancies. It is the most common gynecologic malignancy diagnosed during pregnancy as well as the most common malignancy in pregnancy worldwide. Three percent of cervical cancers are diagnosed during pregnancy. For many women, especially those of lower socioeconomic status, pregnancy may be the only time they receive medical attention. Cervical cancer screening guidelines recommend to start cervical cytology screening at 21 years of age regardless of pregnancy status. The use of Pap tests and gynecologic examination as a component of routine prenatal care likely contributes to the high rate of cervical cancer diagnosis during pregnancy.
Risk factors for the development of cervical cancer in nonpregnant and pregnant populations appear to be similar, with human papilloma virus (HPV) infection, multiple sexual partners, early coitarche, smoking, immunosuppression, human immunodeficiency (HIV) infection, low socioeconomic status, and non-white race associated with higher incidence. Cervical cancers diagnosed during pregnancy tend to be of lower stage, with one study finding a 3.1 relative risk of having stage I disease.61 The histologic spectrum is similar in pregnant and nonpregnant populations, with squamous cell histology predominating.
Diagnosis
The mechanisms to diagnose cervical cancer during pregnancy are the same as those used in nonpregnant patients and include cytology, colposcopy, cervical biopsy, and, in carefully selected cases, cervical conization. The incidence of abnormal cervical cytology in pregnancy is similar to that seen in nonpregnant cohorts, with rates of approximately 5% to 8%. The performance characteristics of cervical cytology do not appear to differ in pregnant and nonpregnant patients. Pregnancy is associated with increased vascularity and altered appearance of the cervix, leading to exaggerated colposcopic findings, which are more difficult to interpret. Thus, if colposcopy is performed during pregnancy, it should be done by a provider with specific expertise in that area. The reliability of expert colposcopic-directed biopsies during pregnancy appears similar to that of the nonpregnant patient, with 83.7% and 89.4% concordance, respectively, with the final diagnosis.62
Cervical biopsies are safe to perform in pregnancy. Despite the increased vascularity of the pregnant cervix, significant hemorrhage rarely occurs. When bleeding does occur, it can usually be controlled by the application of pressure. If necessary, use of Monsel solution to the biopsy site is another alternative for obtaining hemostasis. Suture ligature is rarely required. Use of an endocervical brush to obtain a cytologic specimen is a safe practice,63,64 but endocervical curettage is omitted during pregnancy due to concerns for possible disruption of the pregnancy. Theoretical complications, such as rupture of membranes, are of concern, despite a lack of definitive evidence for this concern. As in nonpregnant patients, any suspicious cervical mass in pregnancy should be biopsied to exclude potential malignancy.
Cervical conization during pregnancy carries considerable risks, including bleeding, miscarriage, preterm labor, preterm delivery, and infection. The incidence of hemorrhage (> 500 cc) with cold knife conization of the cervix is correlated with the trimester during which the procedure is performed; there is minimal risk during the first trimester, 5% in the second trimester, and 10% in the third trimester.65,66 Fetal loss rates are on the order of 4.5%.65,67 Given these risks, cervical conization during pregnancy should only be used when there is strong suspicion for an invasive malignancy based on cytology, cervical biopsy, or colposcopic appearance, and when the diagnosis of invasive malignancy would significantly alter the management of the pregnancy and the timing or route of delivery. In these situations, consideration should be given to performing a cerclage during the conization procedure in pregnancy, whether performed as cold knife conization or loop electrosurgical excision procedure cone.68
Treatment
Abnormal Cervical Cytology and Cervical Dysplasia
Studies indicate a high rate of postpartum regression of abnormal cervical cytology and cervical dysplasia diagnosed in pregnancy. A recent study of 1079 patients who underwent colposcopy during pregnancy, mostly without biopsy (93%), found postpartum regression to normal for 64% of patients referred with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Paps, and 53% for those with high-grade squamous intraepithelial lesion (HSIL) Paps.69 In a study of 153 cases of biopsy-proven cervical intraepithelial neoplasia (CIN) II and CIN III in pregnancy, no cases of progression to invasive or microinvasive disease were found. This study also noted high resolution rates, with 39% of CIN II and 37% of CIN III regressing to normal postpartum.70 In line with these high rates of regression and low rates of progression to invasive disease during pregnancy, the 2006 Bethesda consensus guidelines for the management of abnormal cervical cancer screening tests and CIN favor a conservative approach in the absence of suspected malignancy and aim to avoid treatment during pregnancy.71,72
The management of abnormal Pap tests in pregnancy is summarized in Figure 16-1. ASCUS cytology in pregnancy can be managed the same as in a nonpregnant patient, but colposcopy may be deferred until at least 6 weeks postpartum. For LSIL cytology in pregnancy, the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines state a preference for performing colposcopy during pregnancy, but it is acceptable to defer this until postpartum. For HSIL, atypical squamous cells, cannot rule out a high-grade lesion (ASC-H), and atypical glandular cells (AGC) cytology during pregnancy, colposcopy is recommended. During colposcopy, biopsies should be taken of any lesions suspicious for CIN II/III or cancer. For histo-logic abnormalities, the ASCCP guidelines recommend follow-up without treatment in CIN I, with re-evaluation with cytology and colposcopy postpartum. For CIN II and CIN III, repeat colposcopy and cytology at 12-week intervals during pregnancy is reasonable, or repeat cytology and colposcopy may be deferred to the postpartum period, depending on the index of suspicion and the gestational age. Treatment of CIN during pregnancy is not indicated. The only indication for treatment of cervical neoplasia during pregnancy is invasive cancer.
FIGURE 16-1. Management of an abnormal pap test and cervical intraepithelial neoplasia in pregnancy. Based on the 2006 American Society for Colposcopy and Cervical Pathology/Bethesda Consensus Guidelines.65,66AGC, atypical glandular cells; ASC-H, atypical squamous cells, cannot rule out a high-grade lesion; ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraepithelial lesion; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion.
Invasive Cervical Cancer
Once invasive cervical cancer is confirmed by biopsy, a careful staging examination and MRI are indicated to assess for size of disease, sites of disease involvement, and evidence of metastatic disease. If cervical cancer is diagnosed in a pregnant woman at an advanced gestational age with expected fetal lung maturity, expedited delivery and initiation of definitive treatment should be undertaken. A cervical cancer diagnosis made in a pre-viable undesired pregnancy should be managed with immediate initiation of appropriate definitive therapy and resultant termination. For all other patients, decisions regarding the treatment of cervical cancer diagnosed during pregnancy are more challenging and should involve a multidisciplinary approach and careful consideration of disease stage, the gestational age of the pregnancy, the patient’s wishes regarding the pregnancy, and the patient’s preferences for therapy.
Figure 16-2 provides an overview of management options for patients diagnosed with invasive cervical cancer during pregnancy. When the decision for definitive treatment has been made for a patient who does not desire to continue a previable pregnancy, recommendations and treatment options are generally the same as those in nonpregnant patients. For patients who wish to continue a previable pregnancy and those who have a potentially viable but premature pregnancy, careful individualized balancing of maternal treatment needs and the desire to allow for fetal maturation must be done. In general, immediate treatment is appropriate in cases of locally advanced disease, documented lymph node metastasis, progression of disease during pregnancy, and when desired by the patient. In some cases, neoadjuvant chemotherapy may provide an opportunity to treat the mother while allowing for further fetal maturation and deferring definitive therapy to the immediate postpartum period.
FIGURE 16-2. Possible management options of invasive cervical cancer in pregnancy. LVSI, lymphovascular space invasion.
Stage IA1
Patients with stage IA1 disease diagnosed on cone biopsy with negative margins can be followed for the remainder of the pregnancy and anticipate vaginal delivery. This approach is supported by data in nonpregnant patients and reports of excellent outcomes in women treated with conization in pregnancy for both stage IA1 squamous cell and IA1 adenocarcinoma of the cervix. In a study of 8 women with squamous cell carcinoma treated with conization and managed expectantly throughout pregnancy, no invasive disease was found at the time of postpartum hysterectomy.73 Similarly, in a small study of 4 pregnant women with stage IA1 adenocarcinoma, no residual invasive cancer was found in postdelivery treatment specimens.74 Because there is no convincing evidence suggesting that vaginal delivery in patients with stage IA1 cervical cancer after conization with negative margins compromises outcomes, cesarean section should be reserved for obstetrical indications. In patients requiring cesarean section who do not desire future fertility, consideration may be given to cesarean hysterectomy, bearing in mind the higher morbidity of hysterectomy at the time of cesarean section.
Extrapolating from data in nonpregnant patients, it can be expected that the risk of residual microinvasive disease after conization for apparent stage IA1 disease with a conization margin positive for CIN III is approximately 22%, and the risk of more than microinvasive disease approximates 10%.75 Therefore, it is imperative that pregnant patients with positive cone margins be followed closely during pregnancy and thoroughly evaluated postpartum. Given these risks, we recommend monthly clinical examinations and colposcopy every 3 months during pregnancy. A detailed discussion regarding route of delivery follows. Subsequent treatment for a patient who had been followed through pregnancy after conization for apparent stage IA1 disease with a conization margin positive for CIN III will depend on the patient’s wishes for future fertility and should at a minimum entail repeat conization. If the patient wishes for more definitive therapy, a frozen cone-hysterectomy76 postpartum is a reasonable management option.
Early-Stage Disease: Stages IA2 to IIA
In early-stage patients (stages IA2-IIA) who desire termination of a previable pregnancy and immediate definitive therapy, radical hysterectomy and lymph-adenectomy with the fetus in situ is generally recommended. In this typically young patient population, surgical management as opposed to radiation therapy may be preferable because it may allow for preservation of ovarian function and avoidance of radiation complications such as vaginal stricture and long-term gastrointestinal toxicity. Some authors recommend evacuation of the uterus before radical hysterectomy when the procedure will be performed at greater than 20 weeks.77 This may be accomplished via hysterotomy during the same procedure. Primary radiation treatment with concomitant chemotherapy may be an alternative option for patients with early-stage disease, especially those who are poor surgical candidates. Consideration should be given to the pretreatment injection of a feticidal agent for second-trimester patients to honor possible patient preferences, avoid the possibility of a live birth during the procedure, and reduce the risk of violating legislation surrounding late previable pregnancy termination.78
The operative morbidity and outcomes of radical hysterectomy appear to be similar in pregnant and nonpregnant populations. In a case-control study of 26 patients who underwent radical hysterectomy for the treatment of cervical cancer during pregnancy, there was no difference in operative time, hospital stay, postoperative bladder function, or postoperative complications compared with nonpregnant matched controls. Blood loss was significantly more in the pregnant group, but blood transfusion was no more frequent. There was also no difference in disease status at last contact, with only 1 patient in the pregnant group dead of disease after an average follow-up period of more than 12 years.79
For early-stage patients diagnosed near term and those who choose to delay definitive therapy until after a viable delivery, radical cesarean hysterectomy with lymphadenectomy is generally recommended. In this approach, the patient undergoes a classical cesarean section, the hysterotomy is closed, and a radical hysterectomy and staging lymphadenectomy is performed. Radical cesarean hysterectomy has been shown to be associated with a higher blood loss and need for blood transfusion.80 However, the rates of other operative and postoperative morbidities are acceptable and on par with radical hysterectomy in nonpregnant patients. The benefits of completing delivery and therapy in a timely manner and in a single procedure appear to outweigh the disadvantage of greater blood loss. Ovarian transposition may be considered if intraoperative findings and tumor characteristics place a young patient at high likelihood for requiring radiation treatment.
Locally Advanced Disease: Stages IIB to IVA
In general, the recommended treatment for patients with stage IIB to IVA disease is radiation with concomitant sensitizing chemotherapy. Very few studies have evaluated the management of cervical cancer in pregnancy with radiotherapy or chemoradiation.81-83 In early pregnancy, chemoradiation treatment can commence without prior evacuation of the uterus. In the majority of cases, fetal death is expected to occur within 2 to 3 weeks and abortion by 20 to 45 days after the beginning of radiotherapy.84,85 Data suggest that pregnancy loss during radiation is delayed and occurs less reliably later in gestation. In a series of 14 patients who underwent radiation therapy for cervical cancer during pregnancy, pregnancy loss occurred an average of 33 days after the initiation of treatment in the first trimester and 44 days after initiation of treatment in the second trimester.86 Because of this, some recommended uterine evacuation before initiation of radiotherapy in previable gestations greater than 20 weeks. If hysterotomy is planned for uterine evacuation, lymph-adenectomy may be performed during the same surgical procedure. Medical abortion is another alternative for uterine evacuation and has been successfully used to induce uterine evacuation in cases where radiation therapy resulted in fetal death, but not spontaneous abortion.87 Injection of a selective feticidal agent should be considered not only before pregnancy evacuation procedures, but also before the initiation of chemoradiation for patients in the second trimester, given the potential psychological impact on patient, family, and providers of performing radiotherapy with a live fetus in utero.
For patients with locally advanced disease with a viable premature or a strongly desired previable pregnancy, management decisions are complex and need to take into consideration the impact of delaying definitive therapy for the mother, the role of staging lymphadenectomy and neoadjuvant chemotherapy during the pregnancy, and the morbidity associated with a premature delivery for the child, all discussed in more detail next.
Fortunately, stage IVB disease is very rare in pregnancy. As in nonpregnant patients, a systemic approach to treatment is usually used, with local therapy focused on palliation of symptoms.
Delaying Treatment
The morbidity and mortality associated with preterm delivery is considerable (Table 16-5). Short delays in delivery may have a significant impact on neonatal survival. For example, in infants admitted to the neonatal intensive care unit without congenital abnormalities, the mortality rate is approximately 30% at 25 to 26 weeks, compared with less than 10% at 28 week and less than 2% at 34 to 35 weeks. Although neonatal survival rates have been improving remarkably at US referral centers, neurodevelopmentally intact survival is still problematic for very prematurely born babies.88 Given the risks associated with prematurity, an effort must be made to balance the desire to optimize fetal outcome with the potential risks of delaying treatment for the mother. Data from many case reports, case series, and case-control studies indicate that there is likely minimal maternal risk associated with delaying treatment of cervical cancer when early-stage disease (stages IA-IB1) is diagnosed during the late second or early third trimester of pregnancy. In a review of 129 pregnancies during which cervical cancer therapy was deliberately delayed for 3 to 4 weeks, excellent outcomes were achieved. More than 95% of patients were alive and without evidence of disease at last follow-up (Table 16-6). Given these data, delaying treatment for early-stage cervical cancer until fetal lung maturity is obtained may be a reasonable treatment option for patients who desire to continue their pregnancy. It is unlikely that this carries considerable risk of inferior cancer outcome for the mother. When choosing to delay therapy, close surveillance is imperative. Progression of disease during this period has been observed, portends a poor prognosis, and warrants immediate initiation of treatment. Given these risks, we recommend monthly clinical examinations and colposcopy every 3 months during pregnancy. One of the greatest challenges lies in determining an individual patient’s risk in delaying therapy.
Table 16-5 Neonatal Outcomes of Extremely Preterm Infants88
Table 16-6 Reported Experience With Deliberate Delay of Therapy in Patients With Invasive Cervical Cancer to Allow for Fetal Maturation44
Several authors have advocated operative (laparoscopic or open) lymphadenectomy during pregnancy to gain accurate knowledge regarding lymph node status, which is the most important negative prognostic factor for the mother.89,90 If nodal metastases are found, the recommendation is for pregnancy termination or delivery, with immediate definitive therapy for the mother.
Neoadjuvant Chemotherapy
The administration of neoadjuvant chemotherapy during pregnancy followed by definitive treatment after delivery is another potential treatment option. Theoretically, it can be used to reduce or stabilize tumor size and to control micrometastatic disease while delaying definitive management until after delivery. A meta-analysis that included 2078 nonpregnant patients showed a survival advantage for neoadjuvant chemotherapy using cycles of 14 days or less or cisplatin dose intensities of at least 25 mg/m2/wk.91 There are several case reports in the literature on the use of neoadjuvant chemotherapy with cisplatin alone or in combination regimens for the treatment of cervical cancer in pregnant patients. Maternal outcomes have been variable, but all infants were normal, without congenital abnormalities (Table 16-7).
Table 16-7 Experience With Neoadjuvant Chemotherapy in Pregnancy for Cervical Cancer44
Delivery Route
There are no randomized studies evaluating the mode of delivery and maternal outcomes for patients with cervical cancer in pregnancy. Retrospective and case-control studies have suggested that vaginal delivery through a cervix with microscopic cervical cancer generally does not alter maternal prognosis. For patients with greater than microinvasive cervical cancer, it is generally recommended that delivery should be by cesarean section, as there is concern for infection, hemorrhage, obstructed labor, dissemination of tumor cells caused by dilation of the cervix, and poorer maternal survival. In a matched case-control study of 56 women diagnosed with cervical cancer during pregnancy and 27 diagnosed within 6 months post-partum, 14% experienced recurrence if delivered by cesarean section, compared with 59% who delivered vaginally.92 Although other studies of similar design suggest that route of delivery may have no impact on maternal survival outcome,61,93 there are reports of at least 13 cases of cervical cancer metastasis and recurrence in the episiotomy site after vaginal delivery with a significant associated morbidity and approximately 50% mortality,94 supporting the recommendation for delivery by cesarean section for patients with frankly invasive cervical cancer.
Survival and Prognosis
Survival for women diagnosed with cervical cancer during pregnancy does not appear to be worse than for nonpregnant women. In a study of 40 cervical cancer cases during pregnancy by Zemlickis et al,61 in which pregnant cervical cancer patients were matched by age, stage, and years of diagnosis with nonpregnant cases, 30-year survival rates were similar. Likewise, a case-control study by Van der Vange et al93 involving 44 pregnancy-associated cervical cancers did not show an adverse prognosis for pregnancy-associated cases, with 5-year survival rates of 80% and 82% in pregnant and nonpregnant patients, respectively. The largest reported experience comes from Sweden.95 These authors reported on a total of 18,474 cases of cervical cancer over a 90-year period of time, which included 219 cases occurring in pregnancy. They noted that over the study period the incidence of cervical cancer diagnosed in pregnancy declined, and cases were diagnosed at an earlier stage. Actuarial 10-year survival rates were not different for those diagnosed in pregnancy compared with age-matched controls. In addition, these authors showed that the incidence of second primary cancers did not differ between the groups (5.5% vs. 5.4%).
OVARIAN CANCER
Key Points
1. The majority of malignant ovarian tumors diagnosed in pregnancy are of epithelial histology (and mainly comprise low malignant potential tumors) followed by germ cell tumors.
2. Adjuvant chemotherapy is not commonly indicated with malignant tumors diagnosed during pregnancy, but should be delayed after the first trimester.
3. Pregnancy does not adversely affect the clinical outcome of ovarian cancer.
Epidemiology
An adnexal mass is diagnosed in up to 6% of pregnancies. In a study of 3000 consecutive pregnant patients who underwent ultrasound before 14 weeks’ gestation with visualization of both ovaries, 161 women were found to have simple cysts greater than 2.5 cm in size or complex cysts.96 More than 71% resolved spontaneously; only 4% required intervention, and 3% underwent torsion. Similarly, in a study of 79 pregnant patients found to have adnexal masses greater than 3 cm (out of a prospectively analyzed group of more than 6000 patients), 51% spontaneously resolved, and less than 4% required intervention.97 Data such as these indicate that the majority of adnexal masses in pregnancy are benign, with many cysts being functional and resolving spontaneously by the mid-second trimester and few requiring intervention during pregnancy. Conversely, malignant ovarian tumors during pregnancy are rare, explaining the paucity of reports in the literature. Despite this, ovarian cancer is the second most common gynecologic cancer diagnosed during pregnancy. The incidence of ovarian cancer during pregnancy is estimated at 0.018 to 0.11 per 1000 pregnancies.98
Not surprisingly, the distribution of histology in malignant ovarian tumors in pregnancy is more similar to the distribution of malignant ovarian tumors in young, reproductive-age women than it is to the ovarian cancer population as a whole. A recent population-based study of adnexal masses in pregnancy found that in the 206 malignant and low malignant potential ovarian tumors identified, 79% were epithelial, whereas 16% were germ cell tumors. Of the epithelial tumors, 72% were of low malignant potential. More than 83% of the invasive cancers were stage I, as were 95% of the low malignant potential tumors.99,100 This is in stark contrast to the greater than 50% incidence of advanced-stage disease in the general ovarian cancer population. Additionally, pregnant patients with ovarian cancer tended to be older and were more likely to be non-Hispanic white when compared with pregnant patients without a diagnosis of ovarian cancer.99
Diagnosis
A review of pregnancy-associated ovarian cancer cases noted that 50% of malignant adnexal masses were found on routine ultrasound examination, whereas 31% presented with pain, 15% presented with distention or a mass, and 4% were found incidentally at the time of cesarean section.98 Definitive diagnosis of ovarian cancer requires surgical removal of the mass and pathologic analysis. Great care should be taken when making the decision of observation or surveillance, as undergoing adnexal surgery during pregnancy is not without potential complications. For example, in the first trimester, disruption of the corpus luteum without subsequent pharmacologic supplementation can result in pregnancy loss. Additionally, Leiserowitz et al99 noted an increased risk of prematurity, very low birthweight infants, and an increased length of neonatal hospitalization in patients who underwent surgery for benign ovarian masses in pregnancy. There is also concern that adnexal masses are at risk for torsion during pregnancy or the immediate postpartum period, which could lead to the need for emergent surgery and therefore pose a potential risk to the pregnancy. Estimates on the risk of torsion of an adnexal mass during pregnancy vary widely (1%-15%), but masses 6 to 10 cm in size seem to be at the highest risk for torsion.101,102 In general, many believe that small, asymptomatic adnexal masses with features suggesting a low risk of malignancy can be safely followed during pregnancy.
Care should also be taken not to delay potentially life-saving surgery for a woman based on her pregnancy. In many women with ovarian cancer diagnosed during pregnancy, surgery alone will be the only treatment intervention required during the pregnancy. Masses with ultrasonographic features that are highly suspicious for malignancy (eg, those with solid, mural nodules, thick septations, papillations, or excrescences), a size greater than 8 to 10 cm, rapid growth (> 3.5 cm/wk), and those that persist into the second trimester carry a higher risk of malignancy, and surgical management should be considered.99-102 When possible, it is preferred to perform surgery in the second trimester when organogenesis is complete, the placenta has taken over as the source of progesterone, and the risk of pregnancy loss after surgery is small.103
Treatment
Surgical management of an adnexal mass suspicious for malignancy during pregnancy usually proceeds through laparotomy. This allows for adequate visualization with minimal need to manipulate the uterus. The use of laparoscopy for the surgical management of adnexal pathology during pregnancy is widely reported and usually well tolerated104,105 and may be considered. Abdominopelvic washings should be obtained, just as in nonpregnant cases. In the setting of a mass suspicious for malignancy, salpingo-oophorectomy is recommended as opposed to cystectomy. A frozen-section analysis by pathology should be obtained. The contralateral adnexa and peritoneal surfaces should be carefully inspected and sampled if suspicious lesions are noted. If malignancy is confirmed by pathology, a complete surgical staging procedure should be performed, especially in patients who appear to have stage I disease. If metastatic epithelial ovarian cancer is encountered, complete cytoreduction to no visible residual disease should generally be attempted. In the setting of metastatic germ cell tumors, which are generally highly chemosensitive, the degree of cytoreduction should be carefully considered while weighing the potential risks and benefits for the mother and the fetus of an extensive cytoreductive effort. Even in the setting of advanced-stage disease, surgical tumor debulking rarely requires uterine removal or disruption of the pregnancy. However, especially in women diagnosed in the first trimester of pregnancy and those with advanced-stage disease, termination of pregnancy should be discussed.
Given the favorable histology and stage distribution of ovarian cancer during pregnancy, adjuvant therapy is not commonly required. As previously discussed, the majority of ovarian cancers diagnosed during pregnancy are of low malignant potential and do not require adjuvant chemotherapy. However, in advanced-stage epithelial ovarian cancer, high-risk early-stage epithelial ovarian cancer, and germ cell tumors (with the exception of stage IA dysgerminomas and stage I, grade 1 immature teratomas), adjuvant treatment with chemotherapy is generally recommended.
If adjuvant chemotherapy is required, initiation of treatment should generally be avoided during the first trimester of pregnancy given the risks of pregnancy loss and fetal malformations. Chemotherapy can be administered during the second and third trimesters of pregnancy, and care should be taken to avoid chemotherapy within 3 weeks of anticipated delivery. In patients with early-stage, completely resected disease, delaying chemotherapy until after delivery, especially when a diagnosis has been made in the late second or third trimester, is a reasonable option that allows avoidance of fetal exposure to chemotherapy and is unlikely to be associated with a significant effect on outcome. However, in the setting of advanced-stage disease or the presence of residual disease, we would not recommend delaying the initiation of chemotherapy more than would be considered reasonable in a nonpregnant patient.
The standard first-line adjuvant treatment for epithelial ovarian cancer is a combination regimen of a platinum and a taxane. The use of single-agent platinum may also be considered.106 Studies on chemotherapy during pregnancy for the treatment of epithelial ovarian cancer are rare. A recent review found only 13 reported cases in the literature.98 Although platinum derivatives are the most commonly used chemo-therapeutic agents in pregnancy, as discussed earlier in the section on chemotherapy, data on the use of platinum plus taxane regimens for ovarian cancer during pregnancy remain very limited.107 Data from pregnant cancer patients treated with chemotherapeutic regimens containing taxanes attest to the feasibility of administration of taxanes during the second and third trimester, and no fetal malformations were noted.39 However, given the more limited data on the use of taxanes during pregnancy, many clinicians prefer to administer single-agent platinum chemotherapy during pregnancy and complete adjuvant therapy with a platinum/taxane regimen after delivery to minimize fetal exposure while maximizing maternal outcomes.
For germ cell tumors, the standard chemotherapy regimen used in nonpregnant patients is BEP. There are several case reports of the use of this regimen for ovarian germ cell tumors during pregnancy, including 1 report of a fetal anomaly (ventriculomegaly and cerebral atrophy).108
Given the limited data on the possible long-term fetal effects of exposure to the various chemotherapy regimens during pregnancy, patients must be appropriately counseled in regard to the uncertainty. However, the reports that exist on these regimens in the treatment of ovarian cancer during pregnancy are overall reassuring and support their indicated use in the second and third trimesters.
Survival and Prognosis
There is no evidence that pregnancy adversely affects outcomes in ovarian cancer. To the contrary, the favorable histology and stage distribution of disease are likely responsible for the overall more favorable outcomes for ovarian cancer patients diagnosed during pregnancy compared with that of the general ovarian cancer population. In a population-based study, ovarian cancer–related mortality for those diagnosed in pregnancy was less than 5%.99 A literature review including only epithelial ovarian cancer cases in pregnancy noted a 28% ovarian cancer–related mortality rate.98 For the infants born to women with ovarian cancer during pregnancy, the outlook is also encouraging. A recent single-institution retrospective analysis of patients with ovarian cancer during pregnancy noted that of the 26 intrauterine pregnancies, all delivered healthy full-term infants.109 There were no congenital malformations and no evidence of metastases to the placenta or fetus.
BREAST CANCER
Key Points
1. Similar to nonpregnant young women diagnosed with breast cancer, the majority are infiltrating ductal adenocarcinomas with larger tumor size, higher rates of lymph node metastases, higher tumor grade and stage, and higher rates of estrogen and progesterone receptor (ER and PR) negativity.
2. Mastectomy is generally preferred over lumpectomy to avoid the need for breast radiation.
3. Future pregnancies after a diagnosis of breast cancer appear to be safe in successfully treated women.
Epidemiology
Breast cancer is the most common invasive malignancy diagnosed in pregnancy and complicates approximately 1 in 3000 pregnancies. In women younger than 30 years, up to 20% of breast cancer diagnoses occur during pregnancy or during the first postpartum year.110 As in nonpregnant women, the most common histology of breast cancer in pregnancy is infiltrating ductal adenocarcinoma (approximately 85%). Patients with pregnancy-associated breast cancers tend to have worse clinicopathologic characteristics than the general breast cancer population, including larger tumor size, higher rates of lymph node metastasis and lymphovascular space invasion, higher tumor grade and stage, and higher rates of ER and PR negativity.111 These clinicopathologic findings are similar to those found in non-pregnant, young breast cancer patients, such that the biology of these tumors is more likely related to the age at diagnosis and not the state of pregnancy.112
Evidence also suggests that despite the long-term protective effects of pregnancy and lactation on breast cancer risk, there is a transient increased risk for breast cancer after pregnancy. Albrektsen et al113 reported a transient increase in risk that peaked 3 to 4 years after delivery, followed by a long-term decrease in risk. Wohlfahrt et al114 similarly noted a transient increased risk of breast cancer after delivery in uniparous and biparous women and additionally noted an increased risk of diagnosis at a more advanced stage.
Diagnosis
Diagnosing breast cancer during pregnancy, as well as in lactating women, can be difficult, and delays in diagnosis are unfortunately common. In part, delays may be due to the physical changes of the breast during pregnancy and lactation causing difficulty with physical examination or difficulty with interpretation of diagnostic studies. Additionally, patients themselves may note a change, but may fail to report it to a physician, believing that the change is physiologic, not pathologic. Finally, physicians may not maintain a high enough index of suspicion and may fail to recognize an abnormality. Delays in diagnosis and treatment may at least partially account for some of the adverse features of pregnancy-associated breast cancer, such as larger tumor size and increased nodal involvement.
Although in older studies, delays of 6 months or more were noted, in more contemporary reports, delays are more on the order of 1 to 2 months.111 However, the impact of even a short delay in diagnosis can be very significant. Nettleton et al115 constructed a mathematical model to estimate the increased risk in nodal metastasis (the most important prognostic factor in breast cancer) attributable to treatment delay. They estimated that for a tumor with a 130-day doubling time (considered a moderately growing tumor), a 1-month delay in the treatment of early-stage breast cancer would increase the risk of axillary lymph node involvement by 0.9%. This risk increases to 2.6% for a 3-month delay and to 5.1% for a 6-month delay. Taken in the context of the estimated 4500 cases of pregnancy-associated breast cancer annually in the United States, a 2-month delay in treatment would correspond to an additional 76 cases of lymph node metastases.
The most common presentation for breast cancer in pregnancy is a breast mass. Despite the fact that approximately 80% of breast mass biopsies performed in pregnant women are benign, a high index of suspicion should be maintained, and any mass that persists for 2 to 4 weeks should be further investigated.112,117 Ultrasound is a commonly used initial imaging study for breast masses during pregnancy; it is inexpensive and does not expose the mother or fetus to potentially dangerous radiation. It has demonstrated an excellent ability to distinguish normal breast tissue from a mass in an area of palpable abnormality and can distinguish a cystic versus a solid lesion in the majority of cases.111,117 Mammography during pregnancy is considered safe, with a standard 4-view mammogram of both breasts with abdominal shielding exposing the fetus to only 0.01 to 0.04 cGy.118 However, mammography has been reported to have a higher false-negative rate during pregnancy, largely due to the increased density of breast tissue in pregnancy. Series have shown pregnancy-associated breast cancers to be mammographically visible in as few as 62.5% of cases.119 A more recent large series reported mammographically visible breast cancers in 90% of cases imaged during pregnancy.117 These authors also point to the importance of the complimentary role of ultrasound and mammography, as in those cases where mammography was unable to identify a lesion, ultrasound revealed a suspicious mass. Data on the use of breast MRI during pregnancy is extremely limited.
Masses that are suspicious based on physical examination or imaging findings should be biopsied to establish a definitive diagnosis. Fine-needle aspiration biopsy, core biopsy, incisional biopsy, and excisional biopsy are all techniques than can be performed safely during pregnancy.
Treatment
Treatment of breast cancer during pregnancy largely parallels treatment offered to nonpregnant patients, with surgery, chemotherapy, and radiotherapy all having a potential role in the treatment algorithm. Locoregional treatment is generally accomplished by surgery. Mastectomy has traditionally been preferred to breast-conserving surgery during pregnancy to avoid the need for breast radiation. However, depending on the timing of diagnosis and the patient’s desires, breast-conserving surgery can be performed and radiation can sometimes be deferred until after delivery. Significantly delaying radiation therapy should be carefully considered, as treatment delays are related to worse outcomes. One study has shown worse local control, overall survival, and disease-free survival in patients in whom radiation was delayed greater than 6 months from diagnosis.120
The regional lymph nodes must also be addressed, as their status is critical in treatment planning. In nonpregnant patients, sentinel lymph node biopsy, as opposed to full axillary lymph node dissection, is often performed in patients with early-stage breast cancer with clinically negative axillary lymph nodes. Vital dyes should not be administered to pregnant women; however, radiolabeled colloids are felt to be safe, and recent data demonstrate that the dose of radiation to the fetus is minimal. The use of this technique for breast cancer in pregnancy has not been fully evaluated in clinical trials, and the American Society of Clinical Oncology does not recommend the use of sentinel lymph node biopsy for breast cancer in pregnancy.121 However, a recent series of 12 patients who underwent sentinel lymph node biopsy for breast cancer during pregnancy reported identification of sentinel lymph nodes in all patients. There have been no axillary recurrences in patients with negative sentinel lymph nodes with a median follow-up of 32 months, and there were no fetal malformations attributable to the procedure.122 Similarly, in another small series of 9 pregnant patients (6 with melanoma and 3 with breast cancer) who underwent sentinel lymph node biopsy, there were no adverse reactions and no adverse fetal effects.123 Given such data, as well as the minimal radiation exposure to the fetus for such a procedure,124 the use of sentinel lymph node biopsy in breast cancer during pregnancy may be gaining favor for appropriately selected and informed patients. The recommendations from an international consensus meeting in 2010 include sentinel lymph node biopsy as a treatment option and state “sentinel lymph node biopsy (SLNB) for staging of the regional lymph nodes can be performed safely during pregnancy.”125
The majority of patients with breast cancer in pregnancy meet criteria for adjuvant chemotherapy treatment. Additionally, in patients with advanced disease, the use of neoadjuvant chemotherapy can be considered before surgery, which may also have the added benefit of allowing for timing of surgery and radiation until after delivery. The 3 largest series on the use of chemotherapy for breast cancer during pregnancy come from MD Anderson Cancer Center, a French National Survey, and the pooled experience of 5 London teaching hospitals. In the MD Anderson series, 57 patients were treated prospectively with 5-fluorouracil, doxorubicin, and cyclophosphamide in the adjuvant or neoadjuvant setting. There were no perinatal mortalities. Three children had congenital or chromosomal abnormalities (Down syndrome, club foot, and congenital bilateral ureteral reflux).126 In the French national survey, 20 patients who were treated with various chemotherapy regimens during pregnancy for breast cancer were retrospectively identified and completed questionnaires. The 2 pregnancies where chemotherapy was initiated in the first trimester ended in miscarriage. One of the remaining 18 pregnancies resulted in stillbirth, and there was one perinatal death of the 17 pregnancies that resulted in live births. There were no reports of congenital abnormalities.127 Similarly, the series from London reported no serious neonatal consequences in the 23 pregnancies where chemotherapy was administered after the first trimester.34
Data on the use of biologic agents during pregnancy are minimal. There are reports on the use of trastuzumab, which has shown benefit in HER2-overexpressing breast cancer, during pregnancy; however, oligohydramnios and anhydramnios are common occurrences (> 50% of reported cases).128 Lapatinib has also been reported in a single pregnancy, with no adverse consequences noted.129 The use of selective estrogen receptor modulators such as tamoxifen during pregnancy has been associated with teratogenic effects in mice, and birth defects have been reported in the offspring of women taking tamoxifen during pregnancy. Their use is not recommended during pregnancy.125
Survival and Prognosis
Studies in which pregnancy-associated breast cancer patients are matched for age and stage with non– pregnancy-associated breast cancer patients indicate that those diagnosed in pregnancy do not have an inferior prognosis.130,131A recent large report that included 652 breast cancer patients diagnosed at less than 35 years of age found that the patients with pregnancy-associated breast cancer did not have an inferior locoregional recurrence-free survival, distant metastasis-free survival, or overall survival compared with patients with breast cancers that were not associated with pregnancy, despite having a higher T classification, N classification, and stage at diagnosis.110 Outcomes for pregnancy-associated breast cancer patients are poor in comparison with those of the general breast cancer population, but this is likely due to tumor factors related to the young age at diagnosis and not pregnancy itself. Termination of pregnancy does not appear to improve outcomes in breast cancer diagnosed during pregnancy.
Although there is a lack of prospective studies on the effects of additional pregnancies on survival outcomes in breast cancer patients, it is the general consensus that future pregnancies are safe for women who have been successfully treated for breast cancer. Many retrospective studies have found that women who become pregnant after treatment for breast cancer do not have worse outcomes.132,133 Some studies, including a recent large meta-analysis, indicate that women who become pregnant after treatment may have improved outcomes.134-136 Many clinicians recommend that patients avoid pregnancy for 2 years after treatment. The risk of recurrent disease is greatest during the first 2 years after treatment. The recommendation to delay future pregnancies stems more from the concern that a coincident pregnancy could complicate treatment options for recurrent disease than from concerns that the pregnancy will negatively impact the woman’s outcome.
MELANOMA
Key Points
1. Malignant melanoma is the most common malignancy found in metastases to the placenta or fetus.
2. Excisional, rather than shave, biopsy should be performed in pregnant women with lesions suspicious for melanoma.
3. Pregnancy does not appear to independently influence clinical outcome in women diagnosed with melanoma.
Epidemiology
The incidence of melanoma is rising. Approximately 30% to 35% of women with melanoma are of child-bearing age, and approximately 1% of female melanoma patients are pregnant. Melanoma represents approximately 8% of cancers diagnosed during pregnancy, with an estimated incidence of 0.1 to 0.28 per 1000 pregnancies.137 In a recent population-based study from Norway, melanoma represented 31% of all malignancies diagnosed during pregnancy,2 highlighting the importance of population-specific awareness of cancer risks.
Malignant melanoma is the most common malignancy found in metastases to the placenta or fetus. A recent review described malignant melanoma as the involved cancer in 24 of 77 cases (31%) of placental metastasis and in 6 of 15 cases (40%) of fetal metastasis.137 Accurate assessment of the incidence of placental or fetal metastases in pregnant patients with melanoma is not available. Given the risk exists and its potential implications for diagnosis and treatment of the baby, it is recommended that the placentas of all pregnancies complicated by a diagnosis of maternal cancer, especially malignant melanoma, be sent to pathology for full evaluation for possible metastatic disease.
Although malignant melanoma is not considered a hormonally dependent tumor, much research has been conducted evaluating the potential impact of hormones on malignant melanoma. The common occurrence of increased pigmentation associated with pregnancy and, less commonly, with exogenous estrogen use (eg, melasma, darkening of the linea nigra) is likely partially responsible for concerns regarding the potential impact of pregnancy, oral contraceptives, and hormone therapy on the development, prognosis, and recurrence risk of melanoma. The impact of pregnancy on the prognosis of melanoma will be addressed in the discussion of survival and prognosis of melanoma in pregnancy. As for oral contraceptives and hormone replacement, there are no conclusive data indicating either an increased risk for developing melanoma or a worsened prognosis.138
Diagnosis
Often, melanoma presents with a change in the size, shape, color, or feel of an existing nevus. During pregnancy, many women note changes in the appearance of nevi. The majority of these lesions are not melanomas, and the changes often disappear after childbirth. However, a high index of suspicion must be maintained to prevent delays in diagnosis during pregnancy. Patients and physicians alike should be aware of the “ABCD” findings suggestive of melanoma and evaluate all suspicious changes: Asymmetry, irregular or blurred Borders, changes in or unevenness of Color, and/or an increase in Diameter of nevi should heighten suspicion. When technically feasible and cosmetically acceptable, an excisional biopsy with a 1- to 2-mm margin of normal skin should be performed and extended into the subcutaneous fat. Shave biopsies should be avoided.139 Incisional or punch biopsy may lead to underestimation of tumor thickness if the thickest portion of the melanoma is not biopsied.
Treatment
After a diagnosis of malignant melanoma is made on biopsy, complete surgical excision with a margin is the standard initial treatment. Guidelines regarding the width of the margin of normal tissue vary based on the thickness of the melanoma. Because of a lack of clear data regarding the ideal surgical margin for tumors of varying thickness, the guidelines between different organizations remain inconsistent.140 In general, for in situ lesions, a 5-mm margin is considered adequate. For tumors of less than 1 mm in thickness, a 1-cm margin is recommended. For tumors of 1- to 4-mm thickness, a 1- to 2-cm margin is recommended. For tumor greater than 4-mm thickness, a 2- to 3-cm margin is recommended.
Sentinel lymph node biopsy is generally recommended for all patients with clinically negative lymph nodes and T2, T3, and T4 disease and select high-risk T1b disease (see Table 16-8 for the melanoma staging system), with full lymph node dissection reserved for patients with clinically positive nodes or positive sentinel lymph node(s). The incidence of positive sentinel lymph nodes varies with the primary tumor thickness and is approximately 4%, 12%, 28%, and 44% for tumor of less than 1 mm, 1.01 to 2 mm, 2.01 to 4 mm, and more than 4 mm.141 The presence of positive lymph nodes is the most important predictor of prognosis. Many believe that pregnancy should not influence the decision to perform sentinel lymph node biopsy with radiolabeled colloids, where recent data demonstrate that the dose of radiation to the fetus is minimal.142 Because it is theoretically possible to have higher fetal exposures when the lesion is located very close to the uterus, some experts recommend decreasing the activity of the tracer and collecting imaging for twice the usual duration as well as minimizing the time interval from injection to operation to further minimize the fetal exposure.142 Complete regional lymphadenectomy is an alternative to sentinel lymph node biopsy.
Table 16-8 TNM Staging of Melanoma
For stage I to IIA disease (≤ T3a, N0, M0), surgical therapy alone is highly curative and adjuvant therapy is not recommended outside of clinical trials. However, for patients with localized stage IIB and above tumors, where the risk of recurrence ranges from 30% to 80%, adjuvant therapy should generally be considered. For nonpregnant patients, treatment with high-dose interferon α is the adjuvant therapy with the most evidence-based support. Despite an initial analysis of the Eastern Cooperative Oncology Group (ECOG) 1684 trial that reported both an improved relapse-free (9-month prolongation) and overall survival (1-year prolongation) for patients who were randomized to receive high-dose interferon α as adjuvant therapy for 1 year,143 a subsequent updated reanalysis of pooled ECOG trials failed to demonstrate an improvement in overall survival, and only the improvement in relapse-free survival remained significant.144 Trials using lower doses of interferon α generally show less or no benefit.145-147 A report from Germany outlines the disease course of a patient who was diagnosed with malignant melanoma during pregnancy and was treated with interferon α from the 8th through 36th weeks of pregnancy.148 She was diagnosed with metastatic disease in the 36th week of pregnancy, underwent induction of labor, and delivered healthy twins. She died 1 year later as a result of her disease. Interferon α has not been shown to cross the placenta and is not teratogenic in animal studies. There is some concern for a possible increased incidence of IUGR in fetus exposed interferon α; however, no causative link has been established. There also does not appear to be an increase in fetal malformations.149 Administration of interferon α in pregnant melanoma patients may be warranted in some circumstances after careful consideration and counseling of the patient regarding the potential risks and benefits. In select situations, adjuvant radiation therapy either to the primary site or to an involved nodal basin may be recommended.150 In a pregnant patient, such a recommendation should take into consideration the distance of the site from the uterus, the gestational age, and the ability to adequately shield and reduce scatter of radiation to the fetus.
In the setting of distant metastasis, prognosis is extremely poor. In nonpregnant patients, dacarbazine is a standard chemotherapy agent for metastatic melanoma and has a response rate of 15% to 25%.151 A randomized trial has shown equivalent activity for dacarbazine and temozolomide, and the later has the advantage of being orally administered.152 Another option for the treatment of metastatic disease is inter-leukin-2 therapy, either alone or in combination with other chemotherapy agents (biochemotherapy). The toxicity of such regimens is significant, and there are no reports of their use during pregnancy.
Survival and Prognosis
Analysis of the American Joint Committee on Cancer Melanoma Staging Database indicates that the most important pathologic prognostic factors in malignant melanoma are tumor thickness, presence or absence of ulceration, mitotic rate, and presence of lymph node metastasis. For a tumor thickness of less than 1 mm, 1.01 to 2 mm, 2.01 to 4 mm, and more than 4 mm, the associated 10-year survival rates are 92%, 80%, 63%, and 50%, respectively. Mitotic rate was the second most powerful pathologic predictor of survival, with the most significant threshold being 1 mitosis/mm2,139 Although some evidence suggests that melanomas diagnosed during pregnancy tend to have a greater thickness, other recent studies do not show such a trend.153,154
Clinical prognostic factors, including older age, male sex, and axial location of the lesion, are associated with a worse prognosis. Beginning in the 1950s, uncontrolled case series indicating worse outcomes in women diagnosed with melanoma during pregnancy caused concern among many clinicians and even led some to recommend surgical sterilization of female melanoma patients. However, more recent controlled studies do not support a negative impact of pregnancy on outcomes in melanoma. O’Meara et al153 performed an analysis of California databases and identified 412 women with melanoma diagnosed during pregnancy 
or within 1 year after pregnancy 
and compared them with a group of age-matched nonpregnant controls. There was no statistically significant impact of pregnancy on survival. In a Swedish database study by Lens et al,154 185 women with melanoma during pregnancy were compared with 5348 women with melanoma who were of childbearing age but were not pregnant. Pregnancy status was not found to be a predictor of survival (hazard ratio, 1.08; 95% CI, 0.60-1.93). In this study, pregnancy after diagnosis was also found to not be a predictor of survival. Other small studies provide additional support that melanoma patients who later become pregnant do not suffer a worse prognosis.155
Most available data regarding the impact of pregnancy on melanoma outcomes deals with patients with localized disease. Data regarding a potential impact of pregnancy on advanced disease is very limited, possibly in part due to many such patients deciding to terminate the pregnancy in the face of advanced, poor-prognosis disease.
THYROID CANCER
Key Points
1. Prior radiation exposure, family history of thyroid cancer or thyroid disease, and irregular menses are risk factors for thyroid cancers diagnosed during pregnancy.
2. Radioactive iodine scanning is contraindicated in pregnancy, and diagnosis should be made with fine-needle aspiration biopsy.
3. Adjuvant postoperative radioiodine ablation should be delayed until after delivery, and lactation is contraindicated.
EPIDEMIOLOGY
Thyroid cancer is the most common endocrine malignancy and is 3 times more common in women than men. It is especially common among women of child-bearing age. Approximately 10% of thyroid cancers in this group are diagnosed during pregnancy or within 1 year after a birth. A recent population-based review noted an incidence of thyroid cancer during pregnancy of 0.14 per 1000 live births.1 Greater than 90% of thyroid cancers belong to the category of differentiated thyroid cancer, which includes papillary and follicular cancers.156 Other less common histologies include anaplastic cancer (thought to arise from differentiated cancers), medullary thyroid cancer, Hürthle cell tumors, and primary thyroid lymphoma.
Exposure to ionizing radiation is a well-established risk factor for the development of thyroid cancer. A population-based case-control study evaluating risk factors for the development of thyroid cancer in pregnancy also noted a family history of thyroid cancer or thyroid disease and irregular menses to be associated with increased risk, but not age of menarche, pregnancy history, or use of oral contraceptive pills.157
Diagnosis
Thyroid cancer most commonly presents with a palpable thyroid mass that is either noted by the patient or found by a physician. It is estimated that approximately 5% of women have a palpable thyroid nodule.156 The incidence of malignancy in a solitary nodule is approximately 8% to 17% in the general population.158 However, reports of thyroid nodules in pregnancy indicate that in the pregnant population this figure may be as high as 39% to 43%.159Thyroid cancer discovered during pregnancy may be more likely to be asymptomatic and found by a physician on routine examination, highlighting the importance of a careful and thorough physical examination during prenatal care.
The work-up of a thyroid mass in pregnancy should proceed along the same lines as in nonpregnant patients, with the exception that radioactive iodine scanning is contraindicated. Ultrasound is a safe and inexpensive tool that can elucidate the size, number, and characteristics of thyroid masses, but cannot rule in or rule out malignancy. It can also be used in the evaluation of the regional lymph nodes.
Fine-needle aspiration biopsy is the diagnostic procedure of choice for the evaluation of thyroid nodules. This can be done either with or without ultrasound guidance, depending on the clinical situation. A recent study indicates that the diagnostic performance of fine-needle aspiration biopsy may be improved by use of ultrasound guidance.160
Treatment
Surgery is generally the primary treatment of choice for thyroid cancer, but at what point the operation should occur when the diagnosis is made during pregnancy is debated. Some advocate for surgery in the second trimester when possible, especially when biopsy indicates an aggressive histology. Most agree that the majority of cancers diagnosed in the third trimester can be observed until after delivery.161 Some even advocate for delaying diagnostic procedures until after delivery in certain clinical situations.162
In a study that included 61 women with thyroid cancer diagnosed during pregnancy, Moosa and Mazzaferri160 found that the tumor size, incidence of nodal metastasis, and risk of recurrence did not differ between patients who underwent surgery during pregnancy compared with those in whom surgery was delayed until after delivery. However, delay in therapy may negatively affect survival. In a study of a group of more than 1300 thyroid cancer patients (men and women), it was noted that the time from diagnosis to initiation of therapy had an independent effect on outcome. Cancer-related mortality was 4% in patients who began therapy within 1 year of diagnosis and 10% in those who began therapy more than a year after diagnosis. Patients who died from their disease had a median delay of 18 months, as opposed to 4 months among cancer survivors.163 In general, the timing of surgery for thyroid cancer in pregnancy should be determined after thoughtful discussion with the patient and should take into account the lesion size, rate of growth, histology, evidence of metastatic disease, gestational age at diagnosis, and the patient’s desires.
Postoperative radioiodine ablation is a commonly used adjuvant treatment for papillary thyroid cancer and has been shown to improve outcomes in many populations of thyroid cancer patients, and it is recommended in a variety of clinical scenarios.156 Because of radiation risks to the fetus or breast-feeding infant, this therapy is reserved until after delivery, and lactation is contraindicated. Papillary cancers express the thyroid-stimulating hormone (TSH) receptor and respond to TSH stimulation with an increase in growth rate. For patients with papillary thyroid cancer with intermediate or high-risk features, suppression of TSH with levothyroxine is recommended,156 as it has been shown to improve clinical outcomes.164 It is also recommended for low-risk patients who have not undergone thyroid remnant ablation.156 When surgical management of papillary thyroid cancer is deferred until after delivery, levothyroxine suppression is recommended during pregnancy.165,166 Dosing should be carefully monitored and adjusted during pregnancy to maintain adequate levels of suppression.
Survival and Prognosis
Although the survival outcomes for thyroid cancer in general are excellent, approximately 20% of patients will have a recurrence. Young age at diagnosis and female sex are associated with good prognosis.164 Several studies indicate that women diagnosed with thyroid cancer during pregnancy have a similar prognosis as that of age-matched controls.167-169 However, the potential stimulatory effects of human chorionic gonadotropin and estrogen on the thyroid gland lead to concerns that the hormonal changes associated with pregnancy may have a negative impact on thyroid cancer prognosis. A recent study indicated a worse prognosis for women diagnosed in pregnancy and also demonstrated increased ERα expression in tumors diagnosed during pregnancy or within 1 year after delivery.170
Pregnancy after successful treatment for thyroid cancer does not seem to be associated with recurrence. In a recent study of 63 women with a history of thyroid cancer, there was no evidence of disease progression during pregnancy in any of the patients who had no evidence of disease before pregnancy. However, there was a strong correlation between the presence of persistent disease before pregnancy and progression during pregnancy. Nearly half of the patients in the study who had evidence of disease before pregnancy had evidence of disease progression during pregnancy.171 Similar findings that pregnancy was unlikely to lead to recurrence, but was associated with progression in patients with known disease before pregnancy, has also been noted by others.172
HEMATOLOGIC MALIGNANCIES
Key Points
1. Hodgkin lymphoma is the most common hemato-logic malignancy in pregnancy.
2. Treatment with chemotherapy should not be delayed in pregnant women with acute myelogenous leukemia.
Epidemiology
Hematologic malignancies account for approximately one-quarter of all malignancies during pregnancy.3 Of the hematologic malignancies, Hodgkin lymphoma (HL) is by far the most common, accounting for more than half of all hematologic malignancies in pregnancy.173 Its incidence in pregnancy is estimated at 1:1000 to 1:6000.3 As in nonpregnant patients, the most common histologic subtype of HL in pregnancy is nodular sclerosis. The etiology of HL is likely multifactorial, involving genetic, immunologic, and environmental factors. Epstein-Barr virus is believed to play a significant role in many cases of HL. Non-Hodgkin lymphoma (NHL) is much less common in pregnancy than HL. When NHL occurs in pregnancy, there may be an association with more aggressive subtypes.174 Outcomes in NHL are worse than those in HL.175
Leukemias occur more rarely in pregnancy, with an estimated incidence of 1 in 75,000-100,000 pregnancies.3 Approximately 90% of leukemias in pregnancy are acute; two-thirds are acute myelogenous leukemia (AML), and one-third are acute lymphocytic leukemia (ALL).173,176 As in HL, a single cause for development of leukemia has not been identified. However, several genetic disorders (eg, Down syndrome, Fanconi anemia), exposure to certain chemotherapeutic agents (eg, alkylating agents), ionizing radiation, and some viruses (eg, HTLV-I, Epstein-Barr virus) have been linked to the development of leukemia.
Diagnosis
HL, in pregnant and nonpregnant patients alike, usually presents with painless lymphadenopathy. Diagnosis is made via lymph node biopsy. Additional work-up includes laboratory studies, bone marrow biopsy, and imaging for staging. In nonpregnant patients, staging imaging with CT scan is generally used. In pregnant patients, a chest x-ray with abdominal shielding and either abdominal ultrasound or MRI to evaluate the liver and spleen and assess for lymphadenopathy are often the imaging studies of choice.
The symptoms of leukemia are nonspecific and overlap with some of the common complaints during pregnancy: fatigue, weakness, dyspnea. Other findings may include easy bruising and epistaxis. Lymphadenopathy, hepatomegaly, and splenomegaly are rare in acute leukemias. Abnormalities in the peripheral blood smear may raise suspicion for leukemia, but the diagnosis is made based on morphologic, immunophenotypic, and cytogenetic studies of a bone marrow sample.173
Treatment
For nonpregnant patients with early-stage HD, combined-modality therapy consisting of epirubicin, bleomycin, vinblastine, and dacarbazine or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by low-dose involved-field radiation therapy has gained strong acceptance given the excellent overall survival rate of 93% reported with this treatment strategy.177 In pregnant patients, several management options exist, and the risks and benefits of each should be carefully considered with the patient and multidisciplinary team. Some advocate that treatment of HD can safely be deferred until after delivery in the majority of cases.178 In 17 cases managed at the BC Cancer Agency, 11 patients received no treatment during pregnancy. Six patients were given single-agent vinblastine to control their disease until term. All reportedly delivered normal babies, and 13 of the 17 are alive at a median of 15 years from delivery.179 Consideration can also be given in select, well-counseled patients to treatment with single-agent chemotherapy during the first trimester with a transition to ABVD in the second trimester or to initial treatment with ABVD starting in the second trimester.180 Radiation therapy for supradiaphragmatic early-stage disease in pregnancy has also been described with acceptable fetal radiation estimates and no reported abnormalities in the offspring.22 Depending on the timing of treatment initiation and response, patients could also be treated with ABVD during the second and third trimester and complete involved-field radiation therapy after delivery.
For patients with advanced-stage HD, multiagent chemotherapy is the preferred treatment, with consideration given to consolidation radiation in some situations. As in early-stage disease, ABVD is generally the preferred multiagent regimen in pregnancy. Mustargen, vincristine, procarbazine, and prednisone (MOPP) is an alternative regimen that has also been used in pregnant patients. If the diagnosis is made in the first trimester, some recommend termination of pregnancy before treatment.180 However, there are reports of successful term deliveries with no congenital malformations in pregnant patients who initiated treatment with the ABVD or MOPP regimens in the first trimester,181and some patients may reasonably elect to continue the pregnancy and initiate treatment in the first trimester. When consolidation radiation is recommended, it is usually deferred until after delivery, especially when targeting infradiaphragmatic disease.
AML is extremely aggressive, and it seems clear that maternal outcomes are significantly compromised when initiation of treatment is delayed. In a recent series, 75% of patients who elected to delay treatment until after delivery died of disease within days of initiating chemotherapy.182 Immediate induction chemotherapy is almost always indicated, with one exception being when diagnosis is made in the late third trimester when immediate delivery before initiation of treatment is an alternative. When diagnosis is made in the first trimester, it is generally recommended that the patient terminate the pregnancy before treatment.
Induction chemotherapy for AML typically includes cytarabine and an anthracycline. Cytarabine is an anti-metabolite and may be teratogenic. Fetal malformations have been reported.38,183 Anthracyclines cross the placenta incompletely, and studies have indicated that only relatively small quantities can be detected in the fetus (100- to 1000-fold less that that seen in adult tissues).39 Doxorubicin is the preferred anthracycline in pregnancy and is not associated with an increased risk for severe congenital malformations.176 Given the cardiotoxicity of anthracyclines, it is reasonable to be concerned about potential long-term cardiac dysfunction in children exposed to anthracyclines in utero. However, a recent study that followed the cardiac function of 81 such children did not show any evidence of late cardiac toxicity.40
Induction chemotherapy is generally followed by consolidation chemotherapy in patients who achieve a complete remission (approximately 30% of young adults) and, in pregnancy, usually includes the same drugs as used for induction. Allogenic hematopoietic stem-cell transplant is an option in those who fail to achieve a complete remission, although there is no reported experience in pregnancy.176
Leukemia and lymphoma have both been found to be metastatic to the placenta and fetus.184 The placenta from pregnancies complicated by hematologic malignancy should be sent for histologic evaluation.
Survival and Prognosis
The modified Ann Arbor disease stage and patient age are the most important prognostic factors in HL. Young patients with early-stage disease have long-term survival rates of more than 90%.173,177 Pregnancy does not appear to adversely affect prognosis. An analysis of pregnancy-associated lymphomas that included 17 cases of HL (stage IIA-IVB) also noted a 5-year survival rate of more than 90%.175 Additionally, a study of 48 patients with HL in pregnancy in which cases were matched for age, stage, and year of treatment revealed no difference in survival for patients with HL in pregnancy. There was also no difference in the stage distribution for patients with HL in pregnancy when compared with the distribution in nonpregnant reproductive-age patients treated for HL at the same institution. Fetal outcomes were also reassuring in this study, with no increased risk for stillbirth, prematurity, IUGR, or fetal malformation noted. There was 1 malformation noted in the group of HL patients: a case of hydrocephaly resulting in neonatal death in a patient exposed to MOPP in the first trimester of pregnancy.185 Birth outcomes for patients with a history of previously treated HL also appear to be excellent. A recent large study that included 192 women who gave birth with a history of HL showed no increased risk of preterm birth, low birthweight at term, stillbirth, or congenital abnormalities.186
In AML, long-term disease-free survival is expected in fewer than 25% of adult cases.187 Pregnancy itself does not appear to adversely affect outcomes in acute leukemia.32,182,188 A recent single-institution series reports an 86% complete response rate for patients newly diagnosed with AML during pregnancy who initiated chemotherapy during the pregnancy. Of these, more than half were long-term survivors.182 Overall, pregnancy outcomes appear to be compromised with premature birth rates greater than 50% and stillbirth in up to 17%.173 The series by Greenlund et al182 reports that in 14 patients who were diagnosed with acute leukemia in pregnancy and elected to continue with the pregnancy, there were 9 live births (5 preterm), 1 spontaneous abortion (4 weeks after diagnosis and before initiation of treatment), 3 IUFDs, and 1 fetal death in association with maternal death. It is difficult to separate effects of the malignancy itself on pregnancy outcomes from the potential effects of treatment.
CONCLUSIONS
A cancer diagnosis during pregnancy remains a relatively rare finding, but in general pregnancy itself does not influence the overall clinical outcome of these women. Individualization of care, with respect to patient wishes, gestational age and viability of the fetus, and stage and grade of the malignancy, remains a critical aspect in the management of malignancy identified during pregnancy. A multidisciplinary approach is often critical to successfully treat these patients to afford excellent outcomes for both mother and infant.
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