Managing Cancer in Pregnancy: Improvements and Considerations

Introduction: Tremendous Progress on Cancer Extends to Cancer in Pregnancy

The biomedical research enterprise that took shape in the United States after World War II has had numerous positive effects, including significant progress made during the past 75-plus years in the diagnosis, prevention, and treatment of cancer.

President Franklin D. Roosevelt’s 1944 request of Dr. Vannevar Bush, director of the then Office of Scientific Research and Development, to organize a program that would advance and apply scientific knowledge for times of peace — just as it been advanced and applied in times of war — culminated in a historic report, Science – The Endless Frontier. Presented in 1945 to President Harry S. Truman, this report helped fuel decades of broad, bold, and coordinated government-sponsored biomedical research aimed at addressing disease and improving the health of the American people (National Science Foundation, 1945).

Discoveries made from research in basic and translational sciences deepened our knowledge of the cellular and molecular underpinnings of cancer, leading to advances in chemotherapy, radiotherapy, and other treatment approaches as well as continual refinements in their application. Similarly, our diagnostic armamentarium has significantly improved.

As a result, we have reduced both the incidence and mortality of cancer. Today, some cancers can be prevented. Others can be reversed or put in remission. Granted, progress has been variable, with some cancers such as ovarian cancer still having relatively low survival rates. Much more needs to be done. Overall, however, the positive effects of the U.S. biomedical research enterprise on cancer are evident. According to the National Cancer Institute’s most recent report on the status of cancer, death rates from cancer fell 1.9% per year on average in females from 2015 to 2019 (Cancer. 2022 Oct 22. doi: 10.1002/cncr.34479).

It is not only patients whose cancer occurs outside of pregnancy who have benefited. When treatment is appropriately selected and timing considerations are made, patients whose cancer is diagnosed during pregnancy — and their children — can have good outcomes.

To explain how the management of cancer in pregnancy has improved, we have invited Gautam G. Rao, MD, gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to write this installment of the Master Class in Obstetrics. As Dr. Rao explains, radiation is not as dangerous to the fetus as once thought, and the safety of many chemotherapeutic regimens in pregnancy has been documented. Obstetricians can and should counsel patients, he explains, about the likelihood of good maternal and fetal outcomes.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].

 

Managing Cancer in Pregnancy

Cancer can cause fear and distress for any patient, but when cancer is diagnosed during pregnancy, an expectant mother fears not only for her own health but for the health of her unborn child. Fortunately, ob.gyn.s and multidisciplinary teams have good reason to reassure patients about the likelihood of good outcomes.

Cancer treatment in pregnancy has improved with advancements in imaging and chemotherapy, and while maternal and fetal outcomes of prenatal cancer treatment are not well reported, evidence acquired in recent years from case series and retrospective studies shows that most imaging studies and procedural diagnostic tests – and many treatments – can be performed safely in pregnancy.

Decades ago, we avoided CT scans during pregnancy because of concerns about radiation exposure to the fetus, leaving some patients without an accurate staging of their cancer. Today, we have evidence that a CT scan is generally safe in pregnancy. Similarly, the safety of many chemotherapeutic regimens in pregnancy has been documented in recent decades,and the use of chemotherapy during pregnancy has increased progressively. Radiation is also commonly utilized in the management of cancers that may occur during pregnancy, such as breast cancer.¹

Considerations of timing are often central to decision-making; chemotherapy and radiotherapy are generally avoided in the first trimester to prevent structural fetal anomalies, for instance, and delaying cancer treatment is often warranted when the patient is a few weeks away from delivery. On occasion, iatrogenic preterm birth is considered when the risks to the mother of delaying a necessary cancer treatment outweigh the risks to the fetus of prematurity.¹

Pregnancy termination is rarely indicated, however, and information gathered over the past 2 decades suggests that fetal and placental metastases are rare.¹ There is broad agreement that prenatal treatment of cancer in pregnancy should adhere as much as possible to protocols and guidelines for nonpregnant patients and that treatment delays driven by fear of fetal anomalies and miscarriage are unnecessary.
 

Cancer Incidence, Use of Diagnostic Imaging

Data on the incidence of cancer in pregnancy comes from population-based cancer registries, and unfortunately, these data are not standardized and are often incomplete. Many studies include cancer diagnosed up to 1 year after pregnancy, and some include preinvasive disease. Estimates therefore vary considerably (see Table 1 for a sampling of estimates incidences.)

It has been reported, and often cited in the literature, that invasive malignancy complicates one in 1,000 pregnancies and that the incidence of cancer in pregnancy (invasive and noninvasive malignancies) has been rising over time.⁸ Increasing maternal age is believed to be playing a role in this rise; as women delay childbearing, they enter the age range in which some cancers become more common. Additionally, improvements in screening and diagnostics have led to earlier cancer detection. The incidence of ovarian neoplasms found during pregnancy has increased, for instance, with the routine use of diagnostic ultrasound in pregnancy.¹

Among the studies showing an increased incidence of pregnancy-associated cancer is a population-based study in Australia, which found that from 1994 to 2007 the crude incidence of pregnancy-associated cancer increased from 112.3 to 191.5 per 100,000 pregnancies (P < .001).⁹ A cohort study in the United States documented an increase in incidence from 75.0 per 100,000 pregnancies in 2002 to 138.5 per 100,000 pregnancies in 2012.¹⁰

Overall, the literature shows us that the skin, cervix, and breast are also common sites for malignancy during pregnancy.¹ According to a 2022 review, breast cancer during pregnancy is less often hormone receptor–positive and more frequently triple negative compared with age-matched controls.¹¹ The frequencies of other pregnancy-associated cancers appear overall to be similar to that of cancer occurring in all women across their reproductive years.¹

Too often, diagnosis is delayed because cancer symptoms can be masked by or can mimic normal physiological changes in pregnancy. For instance, breast cancer can be difficult to diagnose during pregnancy and lactation due to anatomic changes in the breast parenchyma. Several studies published in the 1990s showed that breast cancer presents at a more advanced stage in pregnant patients than in nonpregnant patients because of this delay.¹ Skin changes suggestive of melanoma can be attributed to hyperpigmentation of pregnancy, for instance. Several observational studies have suggested that thicker melanomas found in pregnancy may be because of delayed diagnosis.⁸

It is important that we thoroughly investigate signs and symptoms suggestive of a malignancy and not automatically attribute these symptoms to the pregnancy itself. Cervical biopsy of a mass or lesion suspicious for cervical cancer can be done safely during pregnancy and should not be delayed or deferred.

Fetal radiation exposure from radiologic examinations has long been a concern, but we know today that while the imaging modality should be chosen to minimize fetal radiation exposure, CT scans and even PET scans should be performed if these exams are deemed best for evaluation. Embryonic exposure to a dose of less than 50 mGy is rarely if at all associated with fetal malformations or miscarriage and a radiation dose of 100 mGy may be considered a floor for consideration of therapeutic termination of pregnancy.^1,8

CT exams are associated with a fetal dose far less than 50 mGy (see Table 2 for radiation doses).

Magnetic resonance imaging with a magnet strength of 3 Tesla or less in any trimester is not associated with an increased risk of harm to the fetus or in early childhood, but the contrast agent gadolinium should be avoided in pregnancy as it has been associated with an increased risk of stillbirth, neonatal death, and childhood inflammatory, rheumatologic, and infiltrative skin lesions.^1,8,12

 

Chemotherapy, Surgery, and Radiation in Pregnancy

The management of cancer during pregnancy requires a multidisciplinary team including medical, gynecologic, or radiation oncologists, and maternal-fetal medicine specialists (Figure 1). Prematurity and low birth weight are frequent complications for fetuses exposed to chemotherapy, although there is some uncertainty as to whether the treatment is causative. However, congenital anomalies no longer are a major concern, provided that drugs are appropriately selected and that fetal exposure occurs during the second or third trimester.

For instance, alkylating agents including cisplatin (an important drug in the management of gynecologic malignancies) have been associated with congenital anomalies in the first trimester but not in the second and third trimesters, and a variety of antimetabolites — excluding methotrexate and aminopterin — similarly have been shown to be relatively safe when used after the first trimester.¹

Small studies have shown no long-term effects of chemotherapy exposure on postnatal growth and long-term neurologic/neurocognitive function,¹ but this is an area that needs more research.

Also in need of investigation is the safety of newer agents in pregnancy. Data are limited on the use of new targeted treatments, monoclonal antibodies, and immunotherapies in pregnancy and their effects on the fetus, with current knowledge coming mainly from single case reports.¹³

Until more is learned — a challenge given that pregnant women are generally excluded from clinical trials — management teams are generally postponing use of these therapies until after delivery. Considering the pace of new developments revolutionizing cancer treatment, this topic will likely get more complex and confusing before we begin acquiring sufficient knowledge.

The timing of surgery for malignancy in pregnancy is similarly based on the balance of maternal and fetal risks, including the risk of maternal disease progression, the risk of preterm delivery, and the prevention of fetal metastases. In general, the safest time is the second trimester.

Maternal surgery in the third trimester may be associated with a risk of premature labor and altered uteroplacental perfusion. A 2005 systematic review of 12,452 women who underwent nonobstetric surgery during pregnancy provides some reassurance, however; compared with the general obstetric population, there was no increase in the rate of miscarriage or major birth defects.¹⁴

Radiotherapy used to be contraindicated in pregnancy but many experts today believe it can be safely utilized provided the uterus is out of field and is protected from scattered radiation. The head, neck, and breast, for instance, can be treated with newer radiotherapies, including stereotactic ablative radiation therapy.⁸ Patients with advanced cervical cancer often receive chemotherapy during pregnancy to slow metastatic growth followed by definitive treatment with postpartum radiation or surgery.

More research is needed, but available data on maternal outcomes are encouraging. For instance, there appear to be no significant differences in short- and long-term complications or survival between women who are pregnant and nonpregnant when treated for invasive cervical cancer.⁸ Similarly, while earlier studies of breast cancer diagnosed during pregnancy suggested a poor prognosis, data now show similar prognoses for pregnant and nonpregnant patients when controlled for stage.¹

Dr. Rao is a gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. He reported no relevant disclosures.

References

1. Rao GG. Chapter 42. Clinical Obstetrics: The Fetus & Mother, 4th ed. Reece EA et al. (eds): 2021.

2. Bannister-Tyrrell M et al. Aust N Z J Obstet Gynaecol. 2014;55:116-122.

3. Oehler MK et al. Aust N Z J Obstet Gynaecol. 2003;43(6):414-420.

4. Ruiz R et al. Breast. 2017;35:136-141. doi: 10.1016/j.breast.2017.07.008.

5. Nolan S et al. Am J Obstet Gynecol. 2019;220(1):S480. doi: 10.1016/j.ajog.2018.11.752.

6. El-Messidi A et al. J Perinat Med. 2015;43(6):683-688. doi: 10.1515/jpm-2014-0133.

7. Pellino G et al. Eur J Gastroenterol Hepatol. 2017;29(7):743-753. doi: 10.1097/MEG.0000000000000863.

8. Eastwood-Wilshere N et al. Asia-Pac J Clin Oncol. 2019;15:296-308.

9. Lee YY et al. BJOG. 2012;119(13):1572-1582.

10. Cottreau CM et al. J Womens Health (Larchmt). 2019 Feb;28(2):250-257.

11. Boere I et al. Best Pract Res Clin Obstet Gynaecol. 2022;82:46-59.

12. Ray JG et al. JAMA 2016;316(9):952-961.

13. Schwab R et al. Cancers. (Basel) 2021;13(12):3048.

14. Cohen-Kerem et al. Am J Surg. 2005;190(3):467-473.

Introduction: Tremendous Progress on Cancer Extends to Cancer in Pregnancy

The biomedical research enterprise that took shape in the United States after World War II has had numerous positive effects, including significant progress made during the past 75-plus years in the diagnosis, prevention, and treatment of cancer.

President Franklin D. Roosevelt’s 1944 request of Dr. Vannevar Bush, director of the then Office of Scientific Research and Development, to organize a program that would advance and apply scientific knowledge for times of peace — just as it been advanced and applied in times of war — culminated in a historic report, Science – The Endless Frontier. Presented in 1945 to President Harry S. Truman, this report helped fuel decades of broad, bold, and coordinated government-sponsored biomedical research aimed at addressing disease and improving the health of the American people (National Science Foundation, 1945).

Discoveries made from research in basic and translational sciences deepened our knowledge of the cellular and molecular underpinnings of cancer, leading to advances in chemotherapy, radiotherapy, and other treatment approaches as well as continual refinements in their application. Similarly, our diagnostic armamentarium has significantly improved.

As a result, we have reduced both the incidence and mortality of cancer. Today, some cancers can be prevented. Others can be reversed or put in remission. Granted, progress has been variable, with some cancers such as ovarian cancer still having relatively low survival rates. Much more needs to be done. Overall, however, the positive effects of the U.S. biomedical research enterprise on cancer are evident. According to the National Cancer Institute’s most recent report on the status of cancer, death rates from cancer fell 1.9% per year on average in females from 2015 to 2019 (Cancer. 2022 Oct 22. doi: 10.1002/cncr.34479).

It is not only patients whose cancer occurs outside of pregnancy who have benefited. When treatment is appropriately selected and timing considerations are made, patients whose cancer is diagnosed during pregnancy — and their children — can have good outcomes.

To explain how the management of cancer in pregnancy has improved, we have invited Gautam G. Rao, MD, gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to write this installment of the Master Class in Obstetrics. As Dr. Rao explains, radiation is not as dangerous to the fetus as once thought, and the safety of many chemotherapeutic regimens in pregnancy has been documented. Obstetricians can and should counsel patients, he explains, about the likelihood of good maternal and fetal outcomes.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].

 

Managing Cancer in Pregnancy

Cancer can cause fear and distress for any patient, but when cancer is diagnosed during pregnancy, an expectant mother fears not only for her own health but for the health of her unborn child. Fortunately, ob.gyn.s and multidisciplinary teams have good reason to reassure patients about the likelihood of good outcomes.

Cancer treatment in pregnancy has improved with advancements in imaging and chemotherapy, and while maternal and fetal outcomes of prenatal cancer treatment are not well reported, evidence acquired in recent years from case series and retrospective studies shows that most imaging studies and procedural diagnostic tests – and many treatments – can be performed safely in pregnancy.

Decades ago, we avoided CT scans during pregnancy because of concerns about radiation exposure to the fetus, leaving some patients without an accurate staging of their cancer. Today, we have evidence that a CT scan is generally safe in pregnancy. Similarly, the safety of many chemotherapeutic regimens in pregnancy has been documented in recent decades,and the use of chemotherapy during pregnancy has increased progressively. Radiation is also commonly utilized in the management of cancers that may occur during pregnancy, such as breast cancer.¹

Considerations of timing are often central to decision-making; chemotherapy and radiotherapy are generally avoided in the first trimester to prevent structural fetal anomalies, for instance, and delaying cancer treatment is often warranted when the patient is a few weeks away from delivery. On occasion, iatrogenic preterm birth is considered when the risks to the mother of delaying a necessary cancer treatment outweigh the risks to the fetus of prematurity.¹

Pregnancy termination is rarely indicated, however, and information gathered over the past 2 decades suggests that fetal and placental metastases are rare.¹ There is broad agreement that prenatal treatment of cancer in pregnancy should adhere as much as possible to protocols and guidelines for nonpregnant patients and that treatment delays driven by fear of fetal anomalies and miscarriage are unnecessary.
 

Cancer Incidence, Use of Diagnostic Imaging

Data on the incidence of cancer in pregnancy comes from population-based cancer registries, and unfortunately, these data are not standardized and are often incomplete. Many studies include cancer diagnosed up to 1 year after pregnancy, and some include preinvasive disease. Estimates therefore vary considerably (see Table 1 for a sampling of estimates incidences.)

It has been reported, and often cited in the literature, that invasive malignancy complicates one in 1,000 pregnancies and that the incidence of cancer in pregnancy (invasive and noninvasive malignancies) has been rising over time.⁸ Increasing maternal age is believed to be playing a role in this rise; as women delay childbearing, they enter the age range in which some cancers become more common. Additionally, improvements in screening and diagnostics have led to earlier cancer detection. The incidence of ovarian neoplasms found during pregnancy has increased, for instance, with the routine use of diagnostic ultrasound in pregnancy.¹

Among the studies showing an increased incidence of pregnancy-associated cancer is a population-based study in Australia, which found that from 1994 to 2007 the crude incidence of pregnancy-associated cancer increased from 112.3 to 191.5 per 100,000 pregnancies (P < .001).⁹ A cohort study in the United States documented an increase in incidence from 75.0 per 100,000 pregnancies in 2002 to 138.5 per 100,000 pregnancies in 2012.¹⁰

Overall, the literature shows us that the skin, cervix, and breast are also common sites for malignancy during pregnancy.¹ According to a 2022 review, breast cancer during pregnancy is less often hormone receptor–positive and more frequently triple negative compared with age-matched controls.¹¹ The frequencies of other pregnancy-associated cancers appear overall to be similar to that of cancer occurring in all women across their reproductive years.¹

Too often, diagnosis is delayed because cancer symptoms can be masked by or can mimic normal physiological changes in pregnancy. For instance, breast cancer can be difficult to diagnose during pregnancy and lactation due to anatomic changes in the breast parenchyma. Several studies published in the 1990s showed that breast cancer presents at a more advanced stage in pregnant patients than in nonpregnant patients because of this delay.¹ Skin changes suggestive of melanoma can be attributed to hyperpigmentation of pregnancy, for instance. Several observational studies have suggested that thicker melanomas found in pregnancy may be because of delayed diagnosis.⁸

It is important that we thoroughly investigate signs and symptoms suggestive of a malignancy and not automatically attribute these symptoms to the pregnancy itself. Cervical biopsy of a mass or lesion suspicious for cervical cancer can be done safely during pregnancy and should not be delayed or deferred.

Fetal radiation exposure from radiologic examinations has long been a concern, but we know today that while the imaging modality should be chosen to minimize fetal radiation exposure, CT scans and even PET scans should be performed if these exams are deemed best for evaluation. Embryonic exposure to a dose of less than 50 mGy is rarely if at all associated with fetal malformations or miscarriage and a radiation dose of 100 mGy may be considered a floor for consideration of therapeutic termination of pregnancy.^1,8

CT exams are associated with a fetal dose far less than 50 mGy (see Table 2 for radiation doses).

Magnetic resonance imaging with a magnet strength of 3 Tesla or less in any trimester is not associated with an increased risk of harm to the fetus or in early childhood, but the contrast agent gadolinium should be avoided in pregnancy as it has been associated with an increased risk of stillbirth, neonatal death, and childhood inflammatory, rheumatologic, and infiltrative skin lesions.^1,8,12

 

Chemotherapy, Surgery, and Radiation in Pregnancy

The management of cancer during pregnancy requires a multidisciplinary team including medical, gynecologic, or radiation oncologists, and maternal-fetal medicine specialists (Figure 1). Prematurity and low birth weight are frequent complications for fetuses exposed to chemotherapy, although there is some uncertainty as to whether the treatment is causative. However, congenital anomalies no longer are a major concern, provided that drugs are appropriately selected and that fetal exposure occurs during the second or third trimester.

For instance, alkylating agents including cisplatin (an important drug in the management of gynecologic malignancies) have been associated with congenital anomalies in the first trimester but not in the second and third trimesters, and a variety of antimetabolites — excluding methotrexate and aminopterin — similarly have been shown to be relatively safe when used after the first trimester.¹

Small studies have shown no long-term effects of chemotherapy exposure on postnatal growth and long-term neurologic/neurocognitive function,¹ but this is an area that needs more research.

Also in need of investigation is the safety of newer agents in pregnancy. Data are limited on the use of new targeted treatments, monoclonal antibodies, and immunotherapies in pregnancy and their effects on the fetus, with current knowledge coming mainly from single case reports.¹³

Until more is learned — a challenge given that pregnant women are generally excluded from clinical trials — management teams are generally postponing use of these therapies until after delivery. Considering the pace of new developments revolutionizing cancer treatment, this topic will likely get more complex and confusing before we begin acquiring sufficient knowledge.

The timing of surgery for malignancy in pregnancy is similarly based on the balance of maternal and fetal risks, including the risk of maternal disease progression, the risk of preterm delivery, and the prevention of fetal metastases. In general, the safest time is the second trimester.

Maternal surgery in the third trimester may be associated with a risk of premature labor and altered uteroplacental perfusion. A 2005 systematic review of 12,452 women who underwent nonobstetric surgery during pregnancy provides some reassurance, however; compared with the general obstetric population, there was no increase in the rate of miscarriage or major birth defects.¹⁴

Radiotherapy used to be contraindicated in pregnancy but many experts today believe it can be safely utilized provided the uterus is out of field and is protected from scattered radiation. The head, neck, and breast, for instance, can be treated with newer radiotherapies, including stereotactic ablative radiation therapy.⁸ Patients with advanced cervical cancer often receive chemotherapy during pregnancy to slow metastatic growth followed by definitive treatment with postpartum radiation or surgery.

More research is needed, but available data on maternal outcomes are encouraging. For instance, there appear to be no significant differences in short- and long-term complications or survival between women who are pregnant and nonpregnant when treated for invasive cervical cancer.⁸ Similarly, while earlier studies of breast cancer diagnosed during pregnancy suggested a poor prognosis, data now show similar prognoses for pregnant and nonpregnant patients when controlled for stage.¹

Dr. Rao is a gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. He reported no relevant disclosures.

References

1. Rao GG. Chapter 42. Clinical Obstetrics: The Fetus & Mother, 4th ed. Reece EA et al. (eds): 2021.

2. Bannister-Tyrrell M et al. Aust N Z J Obstet Gynaecol. 2014;55:116-122.

3. Oehler MK et al. Aust N Z J Obstet Gynaecol. 2003;43(6):414-420.

4. Ruiz R et al. Breast. 2017;35:136-141. doi: 10.1016/j.breast.2017.07.008.

5. Nolan S et al. Am J Obstet Gynecol. 2019;220(1):S480. doi: 10.1016/j.ajog.2018.11.752.

6. El-Messidi A et al. J Perinat Med. 2015;43(6):683-688. doi: 10.1515/jpm-2014-0133.

7. Pellino G et al. Eur J Gastroenterol Hepatol. 2017;29(7):743-753. doi: 10.1097/MEG.0000000000000863.

8. Eastwood-Wilshere N et al. Asia-Pac J Clin Oncol. 2019;15:296-308.

9. Lee YY et al. BJOG. 2012;119(13):1572-1582.

10. Cottreau CM et al. J Womens Health (Larchmt). 2019 Feb;28(2):250-257.

11. Boere I et al. Best Pract Res Clin Obstet Gynaecol. 2022;82:46-59.

12. Ray JG et al. JAMA 2016;316(9):952-961.

13. Schwab R et al. Cancers. (Basel) 2021;13(12):3048.

14. Cohen-Kerem et al. Am J Surg. 2005;190(3):467-473.

Introduction: Tremendous Progress on Cancer Extends to Cancer in Pregnancy

The biomedical research enterprise that took shape in the United States after World War II has had numerous positive effects, including significant progress made during the past 75-plus years in the diagnosis, prevention, and treatment of cancer.

President Franklin D. Roosevelt’s 1944 request of Dr. Vannevar Bush, director of the then Office of Scientific Research and Development, to organize a program that would advance and apply scientific knowledge for times of peace — just as it been advanced and applied in times of war — culminated in a historic report, Science – The Endless Frontier. Presented in 1945 to President Harry S. Truman, this report helped fuel decades of broad, bold, and coordinated government-sponsored biomedical research aimed at addressing disease and improving the health of the American people (National Science Foundation, 1945).

Discoveries made from research in basic and translational sciences deepened our knowledge of the cellular and molecular underpinnings of cancer, leading to advances in chemotherapy, radiotherapy, and other treatment approaches as well as continual refinements in their application. Similarly, our diagnostic armamentarium has significantly improved.

As a result, we have reduced both the incidence and mortality of cancer. Today, some cancers can be prevented. Others can be reversed or put in remission. Granted, progress has been variable, with some cancers such as ovarian cancer still having relatively low survival rates. Much more needs to be done. Overall, however, the positive effects of the U.S. biomedical research enterprise on cancer are evident. According to the National Cancer Institute’s most recent report on the status of cancer, death rates from cancer fell 1.9% per year on average in females from 2015 to 2019 (Cancer. 2022 Oct 22. doi: 10.1002/cncr.34479).

It is not only patients whose cancer occurs outside of pregnancy who have benefited. When treatment is appropriately selected and timing considerations are made, patients whose cancer is diagnosed during pregnancy — and their children — can have good outcomes.

To explain how the management of cancer in pregnancy has improved, we have invited Gautam G. Rao, MD, gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to write this installment of the Master Class in Obstetrics. As Dr. Rao explains, radiation is not as dangerous to the fetus as once thought, and the safety of many chemotherapeutic regimens in pregnancy has been documented. Obstetricians can and should counsel patients, he explains, about the likelihood of good maternal and fetal outcomes.
 

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].

 

Managing Cancer in Pregnancy

Cancer can cause fear and distress for any patient, but when cancer is diagnosed during pregnancy, an expectant mother fears not only for her own health but for the health of her unborn child. Fortunately, ob.gyn.s and multidisciplinary teams have good reason to reassure patients about the likelihood of good outcomes.

Cancer treatment in pregnancy has improved with advancements in imaging and chemotherapy, and while maternal and fetal outcomes of prenatal cancer treatment are not well reported, evidence acquired in recent years from case series and retrospective studies shows that most imaging studies and procedural diagnostic tests – and many treatments – can be performed safely in pregnancy.

Decades ago, we avoided CT scans during pregnancy because of concerns about radiation exposure to the fetus, leaving some patients without an accurate staging of their cancer. Today, we have evidence that a CT scan is generally safe in pregnancy. Similarly, the safety of many chemotherapeutic regimens in pregnancy has been documented in recent decades,and the use of chemotherapy during pregnancy has increased progressively. Radiation is also commonly utilized in the management of cancers that may occur during pregnancy, such as breast cancer.¹

Considerations of timing are often central to decision-making; chemotherapy and radiotherapy are generally avoided in the first trimester to prevent structural fetal anomalies, for instance, and delaying cancer treatment is often warranted when the patient is a few weeks away from delivery. On occasion, iatrogenic preterm birth is considered when the risks to the mother of delaying a necessary cancer treatment outweigh the risks to the fetus of prematurity.¹

Pregnancy termination is rarely indicated, however, and information gathered over the past 2 decades suggests that fetal and placental metastases are rare.¹ There is broad agreement that prenatal treatment of cancer in pregnancy should adhere as much as possible to protocols and guidelines for nonpregnant patients and that treatment delays driven by fear of fetal anomalies and miscarriage are unnecessary.
 

Cancer Incidence, Use of Diagnostic Imaging

Data on the incidence of cancer in pregnancy comes from population-based cancer registries, and unfortunately, these data are not standardized and are often incomplete. Many studies include cancer diagnosed up to 1 year after pregnancy, and some include preinvasive disease. Estimates therefore vary considerably (see Table 1 for a sampling of estimates incidences.)

It has been reported, and often cited in the literature, that invasive malignancy complicates one in 1,000 pregnancies and that the incidence of cancer in pregnancy (invasive and noninvasive malignancies) has been rising over time.⁸ Increasing maternal age is believed to be playing a role in this rise; as women delay childbearing, they enter the age range in which some cancers become more common. Additionally, improvements in screening and diagnostics have led to earlier cancer detection. The incidence of ovarian neoplasms found during pregnancy has increased, for instance, with the routine use of diagnostic ultrasound in pregnancy.¹

Among the studies showing an increased incidence of pregnancy-associated cancer is a population-based study in Australia, which found that from 1994 to 2007 the crude incidence of pregnancy-associated cancer increased from 112.3 to 191.5 per 100,000 pregnancies (P < .001).⁹ A cohort study in the United States documented an increase in incidence from 75.0 per 100,000 pregnancies in 2002 to 138.5 per 100,000 pregnancies in 2012.¹⁰

Overall, the literature shows us that the skin, cervix, and breast are also common sites for malignancy during pregnancy.¹ According to a 2022 review, breast cancer during pregnancy is less often hormone receptor–positive and more frequently triple negative compared with age-matched controls.¹¹ The frequencies of other pregnancy-associated cancers appear overall to be similar to that of cancer occurring in all women across their reproductive years.¹

Too often, diagnosis is delayed because cancer symptoms can be masked by or can mimic normal physiological changes in pregnancy. For instance, breast cancer can be difficult to diagnose during pregnancy and lactation due to anatomic changes in the breast parenchyma. Several studies published in the 1990s showed that breast cancer presents at a more advanced stage in pregnant patients than in nonpregnant patients because of this delay.¹ Skin changes suggestive of melanoma can be attributed to hyperpigmentation of pregnancy, for instance. Several observational studies have suggested that thicker melanomas found in pregnancy may be because of delayed diagnosis.⁸

It is important that we thoroughly investigate signs and symptoms suggestive of a malignancy and not automatically attribute these symptoms to the pregnancy itself. Cervical biopsy of a mass or lesion suspicious for cervical cancer can be done safely during pregnancy and should not be delayed or deferred.

Fetal radiation exposure from radiologic examinations has long been a concern, but we know today that while the imaging modality should be chosen to minimize fetal radiation exposure, CT scans and even PET scans should be performed if these exams are deemed best for evaluation. Embryonic exposure to a dose of less than 50 mGy is rarely if at all associated with fetal malformations or miscarriage and a radiation dose of 100 mGy may be considered a floor for consideration of therapeutic termination of pregnancy.^1,8

CT exams are associated with a fetal dose far less than 50 mGy (see Table 2 for radiation doses).

Magnetic resonance imaging with a magnet strength of 3 Tesla or less in any trimester is not associated with an increased risk of harm to the fetus or in early childhood, but the contrast agent gadolinium should be avoided in pregnancy as it has been associated with an increased risk of stillbirth, neonatal death, and childhood inflammatory, rheumatologic, and infiltrative skin lesions.^1,8,12

 

Chemotherapy, Surgery, and Radiation in Pregnancy

The management of cancer during pregnancy requires a multidisciplinary team including medical, gynecologic, or radiation oncologists, and maternal-fetal medicine specialists (Figure 1). Prematurity and low birth weight are frequent complications for fetuses exposed to chemotherapy, although there is some uncertainty as to whether the treatment is causative. However, congenital anomalies no longer are a major concern, provided that drugs are appropriately selected and that fetal exposure occurs during the second or third trimester.

For instance, alkylating agents including cisplatin (an important drug in the management of gynecologic malignancies) have been associated with congenital anomalies in the first trimester but not in the second and third trimesters, and a variety of antimetabolites — excluding methotrexate and aminopterin — similarly have been shown to be relatively safe when used after the first trimester.¹

Small studies have shown no long-term effects of chemotherapy exposure on postnatal growth and long-term neurologic/neurocognitive function,¹ but this is an area that needs more research.

Also in need of investigation is the safety of newer agents in pregnancy. Data are limited on the use of new targeted treatments, monoclonal antibodies, and immunotherapies in pregnancy and their effects on the fetus, with current knowledge coming mainly from single case reports.¹³

Until more is learned — a challenge given that pregnant women are generally excluded from clinical trials — management teams are generally postponing use of these therapies until after delivery. Considering the pace of new developments revolutionizing cancer treatment, this topic will likely get more complex and confusing before we begin acquiring sufficient knowledge.

The timing of surgery for malignancy in pregnancy is similarly based on the balance of maternal and fetal risks, including the risk of maternal disease progression, the risk of preterm delivery, and the prevention of fetal metastases. In general, the safest time is the second trimester.

Maternal surgery in the third trimester may be associated with a risk of premature labor and altered uteroplacental perfusion. A 2005 systematic review of 12,452 women who underwent nonobstetric surgery during pregnancy provides some reassurance, however; compared with the general obstetric population, there was no increase in the rate of miscarriage or major birth defects.¹⁴

Radiotherapy used to be contraindicated in pregnancy but many experts today believe it can be safely utilized provided the uterus is out of field and is protected from scattered radiation. The head, neck, and breast, for instance, can be treated with newer radiotherapies, including stereotactic ablative radiation therapy.⁸ Patients with advanced cervical cancer often receive chemotherapy during pregnancy to slow metastatic growth followed by definitive treatment with postpartum radiation or surgery.

More research is needed, but available data on maternal outcomes are encouraging. For instance, there appear to be no significant differences in short- and long-term complications or survival between women who are pregnant and nonpregnant when treated for invasive cervical cancer.⁸ Similarly, while earlier studies of breast cancer diagnosed during pregnancy suggested a poor prognosis, data now show similar prognoses for pregnant and nonpregnant patients when controlled for stage.¹

Dr. Rao is a gynecologic oncologist and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. He reported no relevant disclosures.

References

1. Rao GG. Chapter 42. Clinical Obstetrics: The Fetus & Mother, 4th ed. Reece EA et al. (eds): 2021.

2. Bannister-Tyrrell M et al. Aust N Z J Obstet Gynaecol. 2014;55:116-122.

3. Oehler MK et al. Aust N Z J Obstet Gynaecol. 2003;43(6):414-420.

4. Ruiz R et al. Breast. 2017;35:136-141. doi: 10.1016/j.breast.2017.07.008.

5. Nolan S et al. Am J Obstet Gynecol. 2019;220(1):S480. doi: 10.1016/j.ajog.2018.11.752.

6. El-Messidi A et al. J Perinat Med. 2015;43(6):683-688. doi: 10.1515/jpm-2014-0133.

7. Pellino G et al. Eur J Gastroenterol Hepatol. 2017;29(7):743-753. doi: 10.1097/MEG.0000000000000863.

8. Eastwood-Wilshere N et al. Asia-Pac J Clin Oncol. 2019;15:296-308.

9. Lee YY et al. BJOG. 2012;119(13):1572-1582.

10. Cottreau CM et al. J Womens Health (Larchmt). 2019 Feb;28(2):250-257.

11. Boere I et al. Best Pract Res Clin Obstet Gynaecol. 2022;82:46-59.

12. Ray JG et al. JAMA 2016;316(9):952-961.

13. Schwab R et al. Cancers. (Basel) 2021;13(12):3048.

14. Cohen-Kerem et al. Am J Surg. 2005;190(3):467-473.