Expert Commentary

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Fertility preservation and sexual health are main concerns in reproductive-age cancer survivors. Approximately 1% of cancer survivors are younger than age 20 and up to 10% are estimated to be younger than age 45.¹ For many of these survivors, a cancer diagnosis may have occurred prior to their completion of childbearing.

Infertility or premature ovarian failure has been reported in 40% to 80% of cancer survivors due to chemotoxicity-induced accelerated loss of oocytes.² Most gonadotoxic chemotherapeutic agents cause DNA double-strand breaks that cannot be adequately repaired, eventually leading to apoptotic cell death.³ Therefore, any chemotherapeutic agent that induces apoptotic death will cause irreversible depletion of ovarian reserve, since primordial follicles cannot be regenerated.

Alkylating agents, such as cyclophosphamide, have been shown to be most cytotoxic, and young cancer survivors who have received a combination of alkylating agents and abdominopelvic radiation—such as those with Hodgkin’s lymphoma—are at higher risk. Other poor prognostic factors for fertility include a hypothalamic-pituitary radiation dose greater than 30 Gy, an ovarian-uterine radiation dose greater than 5 Gy, summed alkylating agent dose score of 3 to 4 for each agent, and treatment with lomustine or cyclophosphamide.⁴

In general, a woman’s age (which reflects her existing ovarian reserve), type of therapeutic agents used, and duration of therapy impact the posttreatment viability of ovarian function. Despite conflicting information in published literature, medical suppression by gonadotropin-releasing hormone agonists is not effective.

Fertility preservation options in the United States include egg, embryo, and ovarian tissue banking and ovarian transposition and ovarian transplantation.⁵

Oncofertility: Maximizing reproductive potential in cancer patients

In 2006, Dr. Teresa Woodruff of the Feinberg School of Medicine at Northwestern University coined the term oncofertility. Oncofertility is defined by the Merriam-Webster dictionary as “a field concerned with minimizing the negative effects of cancer treatment (such as chemotherapy or radiation) on the reproductive system and fertility and with assisting individuals with reproductive impairments resulting from cancer therapy.”

Recognition of the many barriers to fertility preservation led to the establishment of the Oncofertility Consortium, a multi-institution group that includes Northwestern University, the University of California San Diego, the University of Pennsylvania, the University of Missouri, and Oregon Health and Science University. The Consortium facilitates collaboration between biomedical and social scientists, pediatricians, oncologists, reproductive specialists, educators, social workers, and medical ethicists in an effort to assess the impact of cancer and its treatment on future fertility and reproductive health and to advance knowledge. The Consortium also is a valuable information resource on fertility preservation options for patients, their families, and providers.⁶

The oncofertility program at Northwestern University was established as an interdisciplinary team of oncologists, reproductive health specialists, supportive care staff, and researchers. Reproductive-age women with cancer can participate in a comprehensive interdisciplinary approach to the management of their malignancy with strict planning and coordination of care, if they wish to maintain fertility following treatment. Many hospitals and health care systems have established such programs, recognizing that the need to preserve fertility potential is an essential part of the comprehensive care of a reproductive-age woman undergoing treatment. When a cancer diagnosis is made, prompt referral to a fertility specialist and a multidisciplinary approach to treatment planning are critical to mitigate the negative impact of cancer treatment on fertility and the potential risk of ovarian damage.

Barriers to oncofertility care

Timely referral to fertility specialists may not occur because of lack of a formal oncofertility program or unawareness of available therapeutic options. In some instances, delaying cancer treatment is not feasible. Additionally, many other factors must be considered regarding societal, ethical, and legal implications. But most concerning is the lack of consistent and timely access to funding for fertility preservation by third-party payers. Although some funding options exist, these require both patient awareness and effort to pursue (TABLE).

National legislation does not include provision for this aspect of women’s health, and as of 2017 insurance coverage for oncofertility was mandated only in 2 states, Connecticut and Rhode Island. In New York, Governor Cuomo directed the Department of Financial Services to study how to ensure that New Yorkers can have access to oncofertility services, and legislation is pending in the New York state legislature.⁷

Recently, Cardozo and colleagues reported that 15 states currently require insurers to provide some form of infertility coverage.⁸ By contrast, RESOLVE: The National Infertility Association, reports information on fertility coverage and the status of bills by state on its website (https://resolve.org). For example, in California, Hawaii, Illinois, and Maryland, bills have been proposed and are in various stages of assessment. Connecticut and Rhode Island mandate coverage. As always, details matter. Cardozo and colleagues eloquently point out limitations of coverage based on age and definition of infertility, and potential financial impact.⁸

An actuarial consulting company called NovaRest prepared a document for the state of Maryland in which the estimated expected number of “cases” would amount to 1,327 women and 731 men aged 10 to 44.⁹ These individuals might require oncofertility services. NovaRest estimated that clients could experience up to a 0.4% increase in insurance premiums annually if this program was offered. Similar estimates are reported by other states. In Kentucky and Mississippi, such bills “died in committee.” The American Society for Reproductive Medicine (ASRM) is actively lobbying with partners, including the Coalition to Protect Parenthood After Cancer, to advocate for preservation of fertility.

Oncofertility efforts are moving in the right direction

---

Lucia DiVenere, MA

Drs. Ursillo and Chalas bring attention to an important issue. As technology advances, so do treatment and coverage needs, and so does the need for ongoing physician and patient education.

In 1990, the US Congress passed the Breast and Cervical Cancer Mortality Prevention Act to help ensure that low-income women would have access to screening for these diseases. It took 10 years before Congress passed the Breast and Cervical Cancer Prevention and Treatment Act so that women detected with breast or cervical cancer could be treated. A curious delay, I know.

Today, we seem to be in a similar situation regarding fertility preservation. Cancer treatment is advanced, coverage is available. Fertility-related treatment is now possible, but coverage is nearly absent.

In my research for this commentary, I learned (a little) about ovarian transplantation and translocation. Even that little was enough to see that we live in an amazing new world. Drs. Ursillo and Chalas put out an important call for physicians to learn, to teach their patients, and, especially, to consider fertility preservation options before (when possible) initiating cancer treatment. It also is imperative to consider fertility preservation in young patients who have not yet reached their fertile years. Cancer treatment begun before fertility preservation may mean future irreversible infertility.

They also call for insurers and public programs to cover fertility and fertility preservation as “essential in the comprehensive care” of cancer patients. To the American College of Obstetricians and Gynecologists (ACOG), that means a federal policy that would ensure public and private coverage for every woman, no matter where she lives, her income level, or her employer.

In many ways, this is a difficult time in public policy related to women’s health. With ACOG’s leadership, our physician colleague organizations and patient advocacy groups are fighting hard to retain women’s health protections already in law. At this moment, opportunities are rare for consideration of expansion. But a national solution is the right solution.

Until we reach that goal, we support state efforts to require private health insurers to cover fertility preservation. As Drs. Ursillo and Chalas point out, only 2 states require private insurers to cover fertility preservation treatment. State-by-state efforts are notoriously difficult, unique, and inequitable to patients. Patients in some states simply are luckier than patients in other states. That is not how to solve a health care problem.

As is often the case, employers—in this case big, cutting-edge companies—are leading the way. Recently, an article in the Wall Street Journal (February 7, 2018) described companies that offer fertility treatment coverage to attract potential employees, such as Pinterest, American Express, and Foursquare. This is an important first step that we can build upon, ensuring that coverage includes fertility protection and then leveraging employer coverage experience to influence coverage more broadly.

Big employers may help us find our way, showing just how little inclusion of this coverage relates to premiums; by some estimates, only 0.4%. That is a small investment for enormous results in a patient’s future.

My takeaways from this thoughtful editorial:

• Physicians should educate themselves about fertility preservation options.
• Physicians should educate their patients about the same.
• Physicians should consider these options before initiating treatment.
• We all should advocate for our patients, in this case, national, state, and employer coverage of fertility treatment, including preservation.

---

Ms. DiVenere is Officer, Government and Political Affairs, at the American College of Obstetricians and Gynecologists in Washington, DC. She is an OBG Management Contributing Editor.

The author reports no financial relationships relevant to this article.

We need a joint effort

Most recent statistics support an increase in cancer survivorship over the past decade.¹⁰ This trend likely will continue thanks to greater application of screening and more effective therapies. The use of targeted therapy is on the rise, but it is not applicable for most malignancies at this time, and its effect on fertility is largely unknown. Millennials now constitute the largest group in our population, and delaying childbearing to the late second and third decades is now common. These medical and societal trends will result in more women being interested in fertility preservation.

The ASRM and other organizations are lobbying to support legislation to mandate coverage for oncofertility on a state-by-state basis. Major limitations of this approach include inability to address oncofertility unless such legislation already has been introduced, the lack of impact on individuals residing in other states, and inefficiency of regional lobbying. In addition, those who are self-insured are not subject to state mandates and therefore will not benefit from such coverage mandates. Finally, nuances in the definition of infertility or age-based restrictions may limit access to these services even when mandated.

A cancer diagnosis is always potentially life-threatening and is often perceived as devastating on a personal level. In women of reproductive age, it represents a threat to their future ability to bear children and to ovarian function. These women deserve to have the opportunity to consider all options to maintain fertility, and they should not struggle with difficult financial choices at a time of such extreme stress.

To address this important issue, a 3-pronged approach is called for:

• All providers caring for cancer patients of reproductive age must be aware of fertility preservation and inform patients of these options.
• Cancer survivors and their caretakers must assist in legislative advocacy efforts.
• Nationally mandated coverage must be sought.

A joint effort by the medical community and women advocates is critical to bring attention to this issue in a national forum and provide a solution that benefits all women.

Acknowledgement

The authors express gratitude to Erin Kramer, Government Affairs, American Society for Reproductive Medicine, and Christa Christakis, Executive Director, American College of Obstetricians and Gynecologists District II, for their assistance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Fertility preservation and sexual health are main concerns in reproductive-age cancer survivors. Approximately 1% of cancer survivors are younger than age 20 and up to 10% are estimated to be younger than age 45.¹ For many of these survivors, a cancer diagnosis may have occurred prior to their completion of childbearing.

Infertility or premature ovarian failure has been reported in 40% to 80% of cancer survivors due to chemotoxicity-induced accelerated loss of oocytes.² Most gonadotoxic chemotherapeutic agents cause DNA double-strand breaks that cannot be adequately repaired, eventually leading to apoptotic cell death.³ Therefore, any chemotherapeutic agent that induces apoptotic death will cause irreversible depletion of ovarian reserve, since primordial follicles cannot be regenerated.

Alkylating agents, such as cyclophosphamide, have been shown to be most cytotoxic, and young cancer survivors who have received a combination of alkylating agents and abdominopelvic radiation—such as those with Hodgkin’s lymphoma—are at higher risk. Other poor prognostic factors for fertility include a hypothalamic-pituitary radiation dose greater than 30 Gy, an ovarian-uterine radiation dose greater than 5 Gy, summed alkylating agent dose score of 3 to 4 for each agent, and treatment with lomustine or cyclophosphamide.⁴

In general, a woman’s age (which reflects her existing ovarian reserve), type of therapeutic agents used, and duration of therapy impact the posttreatment viability of ovarian function. Despite conflicting information in published literature, medical suppression by gonadotropin-releasing hormone agonists is not effective.

Fertility preservation options in the United States include egg, embryo, and ovarian tissue banking and ovarian transposition and ovarian transplantation.⁵

Oncofertility: Maximizing reproductive potential in cancer patients

In 2006, Dr. Teresa Woodruff of the Feinberg School of Medicine at Northwestern University coined the term oncofertility. Oncofertility is defined by the Merriam-Webster dictionary as “a field concerned with minimizing the negative effects of cancer treatment (such as chemotherapy or radiation) on the reproductive system and fertility and with assisting individuals with reproductive impairments resulting from cancer therapy.”

Recognition of the many barriers to fertility preservation led to the establishment of the Oncofertility Consortium, a multi-institution group that includes Northwestern University, the University of California San Diego, the University of Pennsylvania, the University of Missouri, and Oregon Health and Science University. The Consortium facilitates collaboration between biomedical and social scientists, pediatricians, oncologists, reproductive specialists, educators, social workers, and medical ethicists in an effort to assess the impact of cancer and its treatment on future fertility and reproductive health and to advance knowledge. The Consortium also is a valuable information resource on fertility preservation options for patients, their families, and providers.⁶

The oncofertility program at Northwestern University was established as an interdisciplinary team of oncologists, reproductive health specialists, supportive care staff, and researchers. Reproductive-age women with cancer can participate in a comprehensive interdisciplinary approach to the management of their malignancy with strict planning and coordination of care, if they wish to maintain fertility following treatment. Many hospitals and health care systems have established such programs, recognizing that the need to preserve fertility potential is an essential part of the comprehensive care of a reproductive-age woman undergoing treatment. When a cancer diagnosis is made, prompt referral to a fertility specialist and a multidisciplinary approach to treatment planning are critical to mitigate the negative impact of cancer treatment on fertility and the potential risk of ovarian damage.

Barriers to oncofertility care

Timely referral to fertility specialists may not occur because of lack of a formal oncofertility program or unawareness of available therapeutic options. In some instances, delaying cancer treatment is not feasible. Additionally, many other factors must be considered regarding societal, ethical, and legal implications. But most concerning is the lack of consistent and timely access to funding for fertility preservation by third-party payers. Although some funding options exist, these require both patient awareness and effort to pursue (TABLE).

National legislation does not include provision for this aspect of women’s health, and as of 2017 insurance coverage for oncofertility was mandated only in 2 states, Connecticut and Rhode Island. In New York, Governor Cuomo directed the Department of Financial Services to study how to ensure that New Yorkers can have access to oncofertility services, and legislation is pending in the New York state legislature.⁷

Recently, Cardozo and colleagues reported that 15 states currently require insurers to provide some form of infertility coverage.⁸ By contrast, RESOLVE: The National Infertility Association, reports information on fertility coverage and the status of bills by state on its website (https://resolve.org). For example, in California, Hawaii, Illinois, and Maryland, bills have been proposed and are in various stages of assessment. Connecticut and Rhode Island mandate coverage. As always, details matter. Cardozo and colleagues eloquently point out limitations of coverage based on age and definition of infertility, and potential financial impact.⁸

An actuarial consulting company called NovaRest prepared a document for the state of Maryland in which the estimated expected number of “cases” would amount to 1,327 women and 731 men aged 10 to 44.⁹ These individuals might require oncofertility services. NovaRest estimated that clients could experience up to a 0.4% increase in insurance premiums annually if this program was offered. Similar estimates are reported by other states. In Kentucky and Mississippi, such bills “died in committee.” The American Society for Reproductive Medicine (ASRM) is actively lobbying with partners, including the Coalition to Protect Parenthood After Cancer, to advocate for preservation of fertility.

Oncofertility efforts are moving in the right direction

---

Lucia DiVenere, MA

Drs. Ursillo and Chalas bring attention to an important issue. As technology advances, so do treatment and coverage needs, and so does the need for ongoing physician and patient education.

In 1990, the US Congress passed the Breast and Cervical Cancer Mortality Prevention Act to help ensure that low-income women would have access to screening for these diseases. It took 10 years before Congress passed the Breast and Cervical Cancer Prevention and Treatment Act so that women detected with breast or cervical cancer could be treated. A curious delay, I know.

Today, we seem to be in a similar situation regarding fertility preservation. Cancer treatment is advanced, coverage is available. Fertility-related treatment is now possible, but coverage is nearly absent.

In my research for this commentary, I learned (a little) about ovarian transplantation and translocation. Even that little was enough to see that we live in an amazing new world. Drs. Ursillo and Chalas put out an important call for physicians to learn, to teach their patients, and, especially, to consider fertility preservation options before (when possible) initiating cancer treatment. It also is imperative to consider fertility preservation in young patients who have not yet reached their fertile years. Cancer treatment begun before fertility preservation may mean future irreversible infertility.

They also call for insurers and public programs to cover fertility and fertility preservation as “essential in the comprehensive care” of cancer patients. To the American College of Obstetricians and Gynecologists (ACOG), that means a federal policy that would ensure public and private coverage for every woman, no matter where she lives, her income level, or her employer.

In many ways, this is a difficult time in public policy related to women’s health. With ACOG’s leadership, our physician colleague organizations and patient advocacy groups are fighting hard to retain women’s health protections already in law. At this moment, opportunities are rare for consideration of expansion. But a national solution is the right solution.

Until we reach that goal, we support state efforts to require private health insurers to cover fertility preservation. As Drs. Ursillo and Chalas point out, only 2 states require private insurers to cover fertility preservation treatment. State-by-state efforts are notoriously difficult, unique, and inequitable to patients. Patients in some states simply are luckier than patients in other states. That is not how to solve a health care problem.

As is often the case, employers—in this case big, cutting-edge companies—are leading the way. Recently, an article in the Wall Street Journal (February 7, 2018) described companies that offer fertility treatment coverage to attract potential employees, such as Pinterest, American Express, and Foursquare. This is an important first step that we can build upon, ensuring that coverage includes fertility protection and then leveraging employer coverage experience to influence coverage more broadly.

Big employers may help us find our way, showing just how little inclusion of this coverage relates to premiums; by some estimates, only 0.4%. That is a small investment for enormous results in a patient’s future.

My takeaways from this thoughtful editorial:

• Physicians should educate themselves about fertility preservation options.
• Physicians should educate their patients about the same.
• Physicians should consider these options before initiating treatment.
• We all should advocate for our patients, in this case, national, state, and employer coverage of fertility treatment, including preservation.

---

Ms. DiVenere is Officer, Government and Political Affairs, at the American College of Obstetricians and Gynecologists in Washington, DC. She is an OBG Management Contributing Editor.

The author reports no financial relationships relevant to this article.

We need a joint effort

Most recent statistics support an increase in cancer survivorship over the past decade.¹⁰ This trend likely will continue thanks to greater application of screening and more effective therapies. The use of targeted therapy is on the rise, but it is not applicable for most malignancies at this time, and its effect on fertility is largely unknown. Millennials now constitute the largest group in our population, and delaying childbearing to the late second and third decades is now common. These medical and societal trends will result in more women being interested in fertility preservation.

The ASRM and other organizations are lobbying to support legislation to mandate coverage for oncofertility on a state-by-state basis. Major limitations of this approach include inability to address oncofertility unless such legislation already has been introduced, the lack of impact on individuals residing in other states, and inefficiency of regional lobbying. In addition, those who are self-insured are not subject to state mandates and therefore will not benefit from such coverage mandates. Finally, nuances in the definition of infertility or age-based restrictions may limit access to these services even when mandated.

A cancer diagnosis is always potentially life-threatening and is often perceived as devastating on a personal level. In women of reproductive age, it represents a threat to their future ability to bear children and to ovarian function. These women deserve to have the opportunity to consider all options to maintain fertility, and they should not struggle with difficult financial choices at a time of such extreme stress.

To address this important issue, a 3-pronged approach is called for:

• All providers caring for cancer patients of reproductive age must be aware of fertility preservation and inform patients of these options.
• Cancer survivors and their caretakers must assist in legislative advocacy efforts.
• Nationally mandated coverage must be sought.

A joint effort by the medical community and women advocates is critical to bring attention to this issue in a national forum and provide a solution that benefits all women.

Acknowledgement

The authors express gratitude to Erin Kramer, Government Affairs, American Society for Reproductive Medicine, and Christa Christakis, Executive Director, American College of Obstetricians and Gynecologists District II, for their assistance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Fertility preservation and sexual health are main concerns in reproductive-age cancer survivors. Approximately 1% of cancer survivors are younger than age 20 and up to 10% are estimated to be younger than age 45.¹ For many of these survivors, a cancer diagnosis may have occurred prior to their completion of childbearing.

Infertility or premature ovarian failure has been reported in 40% to 80% of cancer survivors due to chemotoxicity-induced accelerated loss of oocytes.² Most gonadotoxic chemotherapeutic agents cause DNA double-strand breaks that cannot be adequately repaired, eventually leading to apoptotic cell death.³ Therefore, any chemotherapeutic agent that induces apoptotic death will cause irreversible depletion of ovarian reserve, since primordial follicles cannot be regenerated.

Alkylating agents, such as cyclophosphamide, have been shown to be most cytotoxic, and young cancer survivors who have received a combination of alkylating agents and abdominopelvic radiation—such as those with Hodgkin’s lymphoma—are at higher risk. Other poor prognostic factors for fertility include a hypothalamic-pituitary radiation dose greater than 30 Gy, an ovarian-uterine radiation dose greater than 5 Gy, summed alkylating agent dose score of 3 to 4 for each agent, and treatment with lomustine or cyclophosphamide.⁴

In general, a woman’s age (which reflects her existing ovarian reserve), type of therapeutic agents used, and duration of therapy impact the posttreatment viability of ovarian function. Despite conflicting information in published literature, medical suppression by gonadotropin-releasing hormone agonists is not effective.

Fertility preservation options in the United States include egg, embryo, and ovarian tissue banking and ovarian transposition and ovarian transplantation.⁵

Oncofertility: Maximizing reproductive potential in cancer patients

In 2006, Dr. Teresa Woodruff of the Feinberg School of Medicine at Northwestern University coined the term oncofertility. Oncofertility is defined by the Merriam-Webster dictionary as “a field concerned with minimizing the negative effects of cancer treatment (such as chemotherapy or radiation) on the reproductive system and fertility and with assisting individuals with reproductive impairments resulting from cancer therapy.”

Recognition of the many barriers to fertility preservation led to the establishment of the Oncofertility Consortium, a multi-institution group that includes Northwestern University, the University of California San Diego, the University of Pennsylvania, the University of Missouri, and Oregon Health and Science University. The Consortium facilitates collaboration between biomedical and social scientists, pediatricians, oncologists, reproductive specialists, educators, social workers, and medical ethicists in an effort to assess the impact of cancer and its treatment on future fertility and reproductive health and to advance knowledge. The Consortium also is a valuable information resource on fertility preservation options for patients, their families, and providers.⁶

The oncofertility program at Northwestern University was established as an interdisciplinary team of oncologists, reproductive health specialists, supportive care staff, and researchers. Reproductive-age women with cancer can participate in a comprehensive interdisciplinary approach to the management of their malignancy with strict planning and coordination of care, if they wish to maintain fertility following treatment. Many hospitals and health care systems have established such programs, recognizing that the need to preserve fertility potential is an essential part of the comprehensive care of a reproductive-age woman undergoing treatment. When a cancer diagnosis is made, prompt referral to a fertility specialist and a multidisciplinary approach to treatment planning are critical to mitigate the negative impact of cancer treatment on fertility and the potential risk of ovarian damage.

Barriers to oncofertility care

Timely referral to fertility specialists may not occur because of lack of a formal oncofertility program or unawareness of available therapeutic options. In some instances, delaying cancer treatment is not feasible. Additionally, many other factors must be considered regarding societal, ethical, and legal implications. But most concerning is the lack of consistent and timely access to funding for fertility preservation by third-party payers. Although some funding options exist, these require both patient awareness and effort to pursue (TABLE).

National legislation does not include provision for this aspect of women’s health, and as of 2017 insurance coverage for oncofertility was mandated only in 2 states, Connecticut and Rhode Island. In New York, Governor Cuomo directed the Department of Financial Services to study how to ensure that New Yorkers can have access to oncofertility services, and legislation is pending in the New York state legislature.⁷

Recently, Cardozo and colleagues reported that 15 states currently require insurers to provide some form of infertility coverage.⁸ By contrast, RESOLVE: The National Infertility Association, reports information on fertility coverage and the status of bills by state on its website (https://resolve.org). For example, in California, Hawaii, Illinois, and Maryland, bills have been proposed and are in various stages of assessment. Connecticut and Rhode Island mandate coverage. As always, details matter. Cardozo and colleagues eloquently point out limitations of coverage based on age and definition of infertility, and potential financial impact.⁸

An actuarial consulting company called NovaRest prepared a document for the state of Maryland in which the estimated expected number of “cases” would amount to 1,327 women and 731 men aged 10 to 44.⁹ These individuals might require oncofertility services. NovaRest estimated that clients could experience up to a 0.4% increase in insurance premiums annually if this program was offered. Similar estimates are reported by other states. In Kentucky and Mississippi, such bills “died in committee.” The American Society for Reproductive Medicine (ASRM) is actively lobbying with partners, including the Coalition to Protect Parenthood After Cancer, to advocate for preservation of fertility.

Oncofertility efforts are moving in the right direction

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Lucia DiVenere, MA

Drs. Ursillo and Chalas bring attention to an important issue. As technology advances, so do treatment and coverage needs, and so does the need for ongoing physician and patient education.

In 1990, the US Congress passed the Breast and Cervical Cancer Mortality Prevention Act to help ensure that low-income women would have access to screening for these diseases. It took 10 years before Congress passed the Breast and Cervical Cancer Prevention and Treatment Act so that women detected with breast or cervical cancer could be treated. A curious delay, I know.

Today, we seem to be in a similar situation regarding fertility preservation. Cancer treatment is advanced, coverage is available. Fertility-related treatment is now possible, but coverage is nearly absent.

In my research for this commentary, I learned (a little) about ovarian transplantation and translocation. Even that little was enough to see that we live in an amazing new world. Drs. Ursillo and Chalas put out an important call for physicians to learn, to teach their patients, and, especially, to consider fertility preservation options before (when possible) initiating cancer treatment. It also is imperative to consider fertility preservation in young patients who have not yet reached their fertile years. Cancer treatment begun before fertility preservation may mean future irreversible infertility.

They also call for insurers and public programs to cover fertility and fertility preservation as “essential in the comprehensive care” of cancer patients. To the American College of Obstetricians and Gynecologists (ACOG), that means a federal policy that would ensure public and private coverage for every woman, no matter where she lives, her income level, or her employer.

In many ways, this is a difficult time in public policy related to women’s health. With ACOG’s leadership, our physician colleague organizations and patient advocacy groups are fighting hard to retain women’s health protections already in law. At this moment, opportunities are rare for consideration of expansion. But a national solution is the right solution.

Until we reach that goal, we support state efforts to require private health insurers to cover fertility preservation. As Drs. Ursillo and Chalas point out, only 2 states require private insurers to cover fertility preservation treatment. State-by-state efforts are notoriously difficult, unique, and inequitable to patients. Patients in some states simply are luckier than patients in other states. That is not how to solve a health care problem.

As is often the case, employers—in this case big, cutting-edge companies—are leading the way. Recently, an article in the Wall Street Journal (February 7, 2018) described companies that offer fertility treatment coverage to attract potential employees, such as Pinterest, American Express, and Foursquare. This is an important first step that we can build upon, ensuring that coverage includes fertility protection and then leveraging employer coverage experience to influence coverage more broadly.

Big employers may help us find our way, showing just how little inclusion of this coverage relates to premiums; by some estimates, only 0.4%. That is a small investment for enormous results in a patient’s future.

My takeaways from this thoughtful editorial:

• Physicians should educate themselves about fertility preservation options.
• Physicians should educate their patients about the same.
• Physicians should consider these options before initiating treatment.
• We all should advocate for our patients, in this case, national, state, and employer coverage of fertility treatment, including preservation.

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Ms. DiVenere is Officer, Government and Political Affairs, at the American College of Obstetricians and Gynecologists in Washington, DC. She is an OBG Management Contributing Editor.

The author reports no financial relationships relevant to this article.

We need a joint effort

Most recent statistics support an increase in cancer survivorship over the past decade.¹⁰ This trend likely will continue thanks to greater application of screening and more effective therapies. The use of targeted therapy is on the rise, but it is not applicable for most malignancies at this time, and its effect on fertility is largely unknown. Millennials now constitute the largest group in our population, and delaying childbearing to the late second and third decades is now common. These medical and societal trends will result in more women being interested in fertility preservation.

The ASRM and other organizations are lobbying to support legislation to mandate coverage for oncofertility on a state-by-state basis. Major limitations of this approach include inability to address oncofertility unless such legislation already has been introduced, the lack of impact on individuals residing in other states, and inefficiency of regional lobbying. In addition, those who are self-insured are not subject to state mandates and therefore will not benefit from such coverage mandates. Finally, nuances in the definition of infertility or age-based restrictions may limit access to these services even when mandated.

A cancer diagnosis is always potentially life-threatening and is often perceived as devastating on a personal level. In women of reproductive age, it represents a threat to their future ability to bear children and to ovarian function. These women deserve to have the opportunity to consider all options to maintain fertility, and they should not struggle with difficult financial choices at a time of such extreme stress.

To address this important issue, a 3-pronged approach is called for:

• All providers caring for cancer patients of reproductive age must be aware of fertility preservation and inform patients of these options.
• Cancer survivors and their caretakers must assist in legislative advocacy efforts.
• Nationally mandated coverage must be sought.

A joint effort by the medical community and women advocates is critical to bring attention to this issue in a national forum and provide a solution that benefits all women.

Acknowledgement

The authors express gratitude to Erin Kramer, Government Affairs, American Society for Reproductive Medicine, and Christa Christakis, Executive Director, American College of Obstetricians and Gynecologists District II, for their assistance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.