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Family separations and the intergenerational transmission of trauma
Editor’s Note: Alison M. Heru, MD, the Families in Psychiatry columnist, invited Dr. Reinstein to address this topic.
Growing up, I was always intrigued by the strong emotions that even the mildest separation evoked within me. As a psychiatrist, I now believe that these emotions were related to my family’s difficulty with separation, a concept likely transmitted from my grandmother’s sudden separation as a child.
The political circumstances of the “Kindertransport” and the recent family separation at the southern U.S. border differ, but the Kindertransport is a model for studying the effects of forced parent-child separation and its intergenerational transmission. As a rescue operation that took place immediately before World War II, the Kindertransport was the emigration of approximately 10,000 German Jewish children from Germany and Nazi-occupied countries to England. Even though they were not literally forced, the parents involved were compelled to separate from their children to give their children a chance to survive.
In a recent letter1 published in The New York Times, Eva Yachnes, herself a Kindertransport participant, reflected on the current situation at the southern U.S. border. She alluded to the lifelong effects of her own separation at the age of 6 when emigrating from Vienna to Germany. Personally, as a granddaughter of a Kindertransport participant, I am particularly concerned about the intergenerational transmission of the trauma of family separation.
Since early May 2018, more than 2,000 children have been forcibly separated from their parents after illegally crossing the border. As part of a “zero tolerance policy,” the separation was characterized by the Trump administration as a deterrent to illegal border crossings. Although many Americans are horrified by the news reports about family separation, psychiatrists in particular have expressed concern about this trauma. The American Psychiatric Association issued a statement2 warning that “any forced separation is highly stressful for children and can cause lifelong trauma.” Several weeks later, the APA joined several other mental health organizations in a letter3 calling for the immediate end of enforcement of those policies. In that letter, the organizations said forced separations can cause “an increased risk of ... mental illnesses such as depression, anxiety, and posttraumatic stress disorder.”
What must psychiatrists understand about the impact of childhood trauma? How can psychiatrists approach treatment of children separated from their parents? Are there ways to minimize the risk for intergenerational impact of this trauma?
What do we know?
Childhood trauma is influenced by multiple factors and can be expressed in several ways. According to research,4 the age of the child at the time of traumatic event, the frequency of traumatic experiences, and the degree to which the child’s caretakers were involved in the trauma are factors that influence the extent of psychological damage. This research also suggests that childhood trauma is associated with emotional dysregulation, aggression against self and others, difficulties in attention and dissociation, medical problems, and difficulty with navigating adult interpersonal relationships.
When viewed through the lens of attachment theory, the forced separation of a child from its caretakers is a potent form of childhood trauma. Joanna E. Chambers, MD, summarizes and explains John Bowlby’s attachment theory as a neurobiological system originating from an infant’s connection to the primary caretaker. This connection becomes a lifelong model for all subsequent relationships.
Any traumatic disruptions in the development of this system puts the child at risk of developing “insecure attachment.” This insecure attachment can lead to lifelong emotional problems for the child, affecting the quality of subsequent marital relationships, relationships to children, and the development of personality disorders.
In addition, it correlates to the development of psychiatric illnesses, specifically depression and anxiety. There is also a plausible biological basis for attachment theory. Both oxytocin, a hormone released in human bonding, and social interaction itself have been shown to decrease cortisol levels. Elevated cortisol has been found to negatively affect infant brain development, Dr. Chambers argued.5
Given those significant effects of childhood trauma, it is understandable that there exists a concept of “intergenerational transmission of trauma.” Originating from studies of Holocaust survivors and their descendants, researchers Amy Lehrner, PhD, and Rachel Yehuda, PhD, conceptualize intergenerational transmission of trauma as the intergenerational impact of prenatal PTSD.6 This impact is expressed as a predisposition in the offspring of Holocaust survivors to developing PTSD, difficulties in individuation and separation, higher rates of mood and anxiety disorders, and higher rates of physical health issues.
Although they are complex and clearly multidetermined, Dr. Yehuda and Dr. Lehrner also summarize plausible biological theories for the intergenerational transmission of trauma. Epigenetic differences in the hypothalamic-pituitary-adrenal axis, circadian rhythm, urinary and plasma cortisol levels, glucocorticoid sensitivity, and regulation of the glucocorticoid receptor gene all have been found in Holocaust offspring with parental PTSD, in contrast to offspring without parental PTSD.6
What can we as psychiatrists do?
We are uniquely equipped to take several concrete steps to help mitigate the effects of these traumatic events. Among them, we can:
- Provide opportunities for the child and the family to process their experience. This can be profoundly healing and can help minimize the devastating psychological effects of this separation.
- Become acquainted with the concept of intergenerational transmission of resilience.
- Work with trauma survivors to develop their own personal narratives and cultural rituals surrounding the trauma.6
- Encourage second- and third-generation descendants to engage in artistic expression of the trauma, visit places of importance to their parents, and engage in social and political activism. These are all expressions of resilience in the offspring of trauma victims.6
In summary, recent U.S. political events have caused thousands of children to be forcibly separated from their parents. Those separations are traumatic and can have lifelong psychological implications for the children and their offspring. It is important to provide quality mental health treatment to these children with a specific focus on treating PTSD and processing the traumatic experience. Psychological treatment can help mitigate the effects of the traumatic separation and create a sense of resiliency.
References
1. New York Times. June 20, 2018. “My separation trauma.”
2. American Psychiatric Association statement, May 30, 2018.
3. Letter to the departments of Justice, Health & Human Services, and Homeland Security, June 20, 2018.
4. Child Adolesc Psychiatric Clin N Am. 2003;(12.2):293-318.
5. Psychodynamic Psychiatry. 2017 Dec;45(4):542-63.
6. Psychological Trauma: Theory, Research, Practice, and Policy. 2018 Jan;10(1):22-9.
Dr. Reinstein is a psychiatry attending at Zucker Hillside Hospital of the Northwell Health System, Glen Oaks, New York. Her clinical interests include reproductive psychiatry and family therapy, with a specific focus on maternal mental health. Dr. Reinstein completed her adult psychiatry residency training at Montefiore Hospital/Albert Einstein College of Medicine after graduating from the Albert Einstein College of Medicine and Yeshiva University with a B.A. in biology. She is one of the recipients of the 4th Annual Resident Recognition Award for Excellence in Family Oriented Care.
Editor’s Note: Alison M. Heru, MD, the Families in Psychiatry columnist, invited Dr. Reinstein to address this topic.
Growing up, I was always intrigued by the strong emotions that even the mildest separation evoked within me. As a psychiatrist, I now believe that these emotions were related to my family’s difficulty with separation, a concept likely transmitted from my grandmother’s sudden separation as a child.
The political circumstances of the “Kindertransport” and the recent family separation at the southern U.S. border differ, but the Kindertransport is a model for studying the effects of forced parent-child separation and its intergenerational transmission. As a rescue operation that took place immediately before World War II, the Kindertransport was the emigration of approximately 10,000 German Jewish children from Germany and Nazi-occupied countries to England. Even though they were not literally forced, the parents involved were compelled to separate from their children to give their children a chance to survive.
In a recent letter1 published in The New York Times, Eva Yachnes, herself a Kindertransport participant, reflected on the current situation at the southern U.S. border. She alluded to the lifelong effects of her own separation at the age of 6 when emigrating from Vienna to Germany. Personally, as a granddaughter of a Kindertransport participant, I am particularly concerned about the intergenerational transmission of the trauma of family separation.
Since early May 2018, more than 2,000 children have been forcibly separated from their parents after illegally crossing the border. As part of a “zero tolerance policy,” the separation was characterized by the Trump administration as a deterrent to illegal border crossings. Although many Americans are horrified by the news reports about family separation, psychiatrists in particular have expressed concern about this trauma. The American Psychiatric Association issued a statement2 warning that “any forced separation is highly stressful for children and can cause lifelong trauma.” Several weeks later, the APA joined several other mental health organizations in a letter3 calling for the immediate end of enforcement of those policies. In that letter, the organizations said forced separations can cause “an increased risk of ... mental illnesses such as depression, anxiety, and posttraumatic stress disorder.”
What must psychiatrists understand about the impact of childhood trauma? How can psychiatrists approach treatment of children separated from their parents? Are there ways to minimize the risk for intergenerational impact of this trauma?
What do we know?
Childhood trauma is influenced by multiple factors and can be expressed in several ways. According to research,4 the age of the child at the time of traumatic event, the frequency of traumatic experiences, and the degree to which the child’s caretakers were involved in the trauma are factors that influence the extent of psychological damage. This research also suggests that childhood trauma is associated with emotional dysregulation, aggression against self and others, difficulties in attention and dissociation, medical problems, and difficulty with navigating adult interpersonal relationships.
When viewed through the lens of attachment theory, the forced separation of a child from its caretakers is a potent form of childhood trauma. Joanna E. Chambers, MD, summarizes and explains John Bowlby’s attachment theory as a neurobiological system originating from an infant’s connection to the primary caretaker. This connection becomes a lifelong model for all subsequent relationships.
Any traumatic disruptions in the development of this system puts the child at risk of developing “insecure attachment.” This insecure attachment can lead to lifelong emotional problems for the child, affecting the quality of subsequent marital relationships, relationships to children, and the development of personality disorders.
In addition, it correlates to the development of psychiatric illnesses, specifically depression and anxiety. There is also a plausible biological basis for attachment theory. Both oxytocin, a hormone released in human bonding, and social interaction itself have been shown to decrease cortisol levels. Elevated cortisol has been found to negatively affect infant brain development, Dr. Chambers argued.5
Given those significant effects of childhood trauma, it is understandable that there exists a concept of “intergenerational transmission of trauma.” Originating from studies of Holocaust survivors and their descendants, researchers Amy Lehrner, PhD, and Rachel Yehuda, PhD, conceptualize intergenerational transmission of trauma as the intergenerational impact of prenatal PTSD.6 This impact is expressed as a predisposition in the offspring of Holocaust survivors to developing PTSD, difficulties in individuation and separation, higher rates of mood and anxiety disorders, and higher rates of physical health issues.
Although they are complex and clearly multidetermined, Dr. Yehuda and Dr. Lehrner also summarize plausible biological theories for the intergenerational transmission of trauma. Epigenetic differences in the hypothalamic-pituitary-adrenal axis, circadian rhythm, urinary and plasma cortisol levels, glucocorticoid sensitivity, and regulation of the glucocorticoid receptor gene all have been found in Holocaust offspring with parental PTSD, in contrast to offspring without parental PTSD.6
What can we as psychiatrists do?
We are uniquely equipped to take several concrete steps to help mitigate the effects of these traumatic events. Among them, we can:
- Provide opportunities for the child and the family to process their experience. This can be profoundly healing and can help minimize the devastating psychological effects of this separation.
- Become acquainted with the concept of intergenerational transmission of resilience.
- Work with trauma survivors to develop their own personal narratives and cultural rituals surrounding the trauma.6
- Encourage second- and third-generation descendants to engage in artistic expression of the trauma, visit places of importance to their parents, and engage in social and political activism. These are all expressions of resilience in the offspring of trauma victims.6
In summary, recent U.S. political events have caused thousands of children to be forcibly separated from their parents. Those separations are traumatic and can have lifelong psychological implications for the children and their offspring. It is important to provide quality mental health treatment to these children with a specific focus on treating PTSD and processing the traumatic experience. Psychological treatment can help mitigate the effects of the traumatic separation and create a sense of resiliency.
References
1. New York Times. June 20, 2018. “My separation trauma.”
2. American Psychiatric Association statement, May 30, 2018.
3. Letter to the departments of Justice, Health & Human Services, and Homeland Security, June 20, 2018.
4. Child Adolesc Psychiatric Clin N Am. 2003;(12.2):293-318.
5. Psychodynamic Psychiatry. 2017 Dec;45(4):542-63.
6. Psychological Trauma: Theory, Research, Practice, and Policy. 2018 Jan;10(1):22-9.
Dr. Reinstein is a psychiatry attending at Zucker Hillside Hospital of the Northwell Health System, Glen Oaks, New York. Her clinical interests include reproductive psychiatry and family therapy, with a specific focus on maternal mental health. Dr. Reinstein completed her adult psychiatry residency training at Montefiore Hospital/Albert Einstein College of Medicine after graduating from the Albert Einstein College of Medicine and Yeshiva University with a B.A. in biology. She is one of the recipients of the 4th Annual Resident Recognition Award for Excellence in Family Oriented Care.
Editor’s Note: Alison M. Heru, MD, the Families in Psychiatry columnist, invited Dr. Reinstein to address this topic.
Growing up, I was always intrigued by the strong emotions that even the mildest separation evoked within me. As a psychiatrist, I now believe that these emotions were related to my family’s difficulty with separation, a concept likely transmitted from my grandmother’s sudden separation as a child.
The political circumstances of the “Kindertransport” and the recent family separation at the southern U.S. border differ, but the Kindertransport is a model for studying the effects of forced parent-child separation and its intergenerational transmission. As a rescue operation that took place immediately before World War II, the Kindertransport was the emigration of approximately 10,000 German Jewish children from Germany and Nazi-occupied countries to England. Even though they were not literally forced, the parents involved were compelled to separate from their children to give their children a chance to survive.
In a recent letter1 published in The New York Times, Eva Yachnes, herself a Kindertransport participant, reflected on the current situation at the southern U.S. border. She alluded to the lifelong effects of her own separation at the age of 6 when emigrating from Vienna to Germany. Personally, as a granddaughter of a Kindertransport participant, I am particularly concerned about the intergenerational transmission of the trauma of family separation.
Since early May 2018, more than 2,000 children have been forcibly separated from their parents after illegally crossing the border. As part of a “zero tolerance policy,” the separation was characterized by the Trump administration as a deterrent to illegal border crossings. Although many Americans are horrified by the news reports about family separation, psychiatrists in particular have expressed concern about this trauma. The American Psychiatric Association issued a statement2 warning that “any forced separation is highly stressful for children and can cause lifelong trauma.” Several weeks later, the APA joined several other mental health organizations in a letter3 calling for the immediate end of enforcement of those policies. In that letter, the organizations said forced separations can cause “an increased risk of ... mental illnesses such as depression, anxiety, and posttraumatic stress disorder.”
What must psychiatrists understand about the impact of childhood trauma? How can psychiatrists approach treatment of children separated from their parents? Are there ways to minimize the risk for intergenerational impact of this trauma?
What do we know?
Childhood trauma is influenced by multiple factors and can be expressed in several ways. According to research,4 the age of the child at the time of traumatic event, the frequency of traumatic experiences, and the degree to which the child’s caretakers were involved in the trauma are factors that influence the extent of psychological damage. This research also suggests that childhood trauma is associated with emotional dysregulation, aggression against self and others, difficulties in attention and dissociation, medical problems, and difficulty with navigating adult interpersonal relationships.
When viewed through the lens of attachment theory, the forced separation of a child from its caretakers is a potent form of childhood trauma. Joanna E. Chambers, MD, summarizes and explains John Bowlby’s attachment theory as a neurobiological system originating from an infant’s connection to the primary caretaker. This connection becomes a lifelong model for all subsequent relationships.
Any traumatic disruptions in the development of this system puts the child at risk of developing “insecure attachment.” This insecure attachment can lead to lifelong emotional problems for the child, affecting the quality of subsequent marital relationships, relationships to children, and the development of personality disorders.
In addition, it correlates to the development of psychiatric illnesses, specifically depression and anxiety. There is also a plausible biological basis for attachment theory. Both oxytocin, a hormone released in human bonding, and social interaction itself have been shown to decrease cortisol levels. Elevated cortisol has been found to negatively affect infant brain development, Dr. Chambers argued.5
Given those significant effects of childhood trauma, it is understandable that there exists a concept of “intergenerational transmission of trauma.” Originating from studies of Holocaust survivors and their descendants, researchers Amy Lehrner, PhD, and Rachel Yehuda, PhD, conceptualize intergenerational transmission of trauma as the intergenerational impact of prenatal PTSD.6 This impact is expressed as a predisposition in the offspring of Holocaust survivors to developing PTSD, difficulties in individuation and separation, higher rates of mood and anxiety disorders, and higher rates of physical health issues.
Although they are complex and clearly multidetermined, Dr. Yehuda and Dr. Lehrner also summarize plausible biological theories for the intergenerational transmission of trauma. Epigenetic differences in the hypothalamic-pituitary-adrenal axis, circadian rhythm, urinary and plasma cortisol levels, glucocorticoid sensitivity, and regulation of the glucocorticoid receptor gene all have been found in Holocaust offspring with parental PTSD, in contrast to offspring without parental PTSD.6
What can we as psychiatrists do?
We are uniquely equipped to take several concrete steps to help mitigate the effects of these traumatic events. Among them, we can:
- Provide opportunities for the child and the family to process their experience. This can be profoundly healing and can help minimize the devastating psychological effects of this separation.
- Become acquainted with the concept of intergenerational transmission of resilience.
- Work with trauma survivors to develop their own personal narratives and cultural rituals surrounding the trauma.6
- Encourage second- and third-generation descendants to engage in artistic expression of the trauma, visit places of importance to their parents, and engage in social and political activism. These are all expressions of resilience in the offspring of trauma victims.6
In summary, recent U.S. political events have caused thousands of children to be forcibly separated from their parents. Those separations are traumatic and can have lifelong psychological implications for the children and their offspring. It is important to provide quality mental health treatment to these children with a specific focus on treating PTSD and processing the traumatic experience. Psychological treatment can help mitigate the effects of the traumatic separation and create a sense of resiliency.
References
1. New York Times. June 20, 2018. “My separation trauma.”
2. American Psychiatric Association statement, May 30, 2018.
3. Letter to the departments of Justice, Health & Human Services, and Homeland Security, June 20, 2018.
4. Child Adolesc Psychiatric Clin N Am. 2003;(12.2):293-318.
5. Psychodynamic Psychiatry. 2017 Dec;45(4):542-63.
6. Psychological Trauma: Theory, Research, Practice, and Policy. 2018 Jan;10(1):22-9.
Dr. Reinstein is a psychiatry attending at Zucker Hillside Hospital of the Northwell Health System, Glen Oaks, New York. Her clinical interests include reproductive psychiatry and family therapy, with a specific focus on maternal mental health. Dr. Reinstein completed her adult psychiatry residency training at Montefiore Hospital/Albert Einstein College of Medicine after graduating from the Albert Einstein College of Medicine and Yeshiva University with a B.A. in biology. She is one of the recipients of the 4th Annual Resident Recognition Award for Excellence in Family Oriented Care.
Breastfeeding with the FDA’s novel drugs approved in 2017, and others
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
The use of only one 2017 novel drug (Benznidazole) during breastfeeding has been reported. No reports describing the use of the other drugs while breastfeeding have been located. Nevertheless, exposure of a nursing infant should be considered if the mother is taking any of these drugs.
During the first 2 days after birth, nearly all drugs will be excreted into milk, but the amounts are very small and will probably have no effect on the nursing infant. After the second day, drugs with molecular weights of less than 1,000 g/mol will be excreted into milk. Some drugs with high molecular weights may also be excreted, but they may be digested in the infant’s gut. If a mother is receiving one of the drugs below and is breastfeeding, her infant should be monitored for the most common adverse effects, shown below, that were observed in nonpregnant adults.
Anti-infectives
Benznidazole (MW 260 g/mol). Abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.
Delafloxacin (Baxdela) (MW 441 g/mol). Nausea, diarrhea, headache, transaminase elevations, vomiting.
Glecaprevir / Pibrentasvir (Mavyret) (MWs 839, 1,113 g/mol). Headache, fatigue.
Letermovir (Prevymis) (MW 573 g/mol). Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain.
Meropenem / vaborbactam (Vabomere) (MWs 438, 297 g/mol). Headache, diarrhea.
Ozenoxacin cream (Xepi) (MW 363 g/mol). No relevant adverse reactions.
Sofosbuvir / Velpatasvir / Voxilaprevir (Vosevi) (MWs 529, 883, 869 g/mol). Headache, fatigue, diarrhea, nausea.
Secnidazole (Solosec) (MW 185 g/mol). Headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain. Manufacturer recommends discontinuing breastfeeding for 96 hours after administration of the drug.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, when breastfeeding.]
Abemaciclib (Verzenio) (MW 507 g/mol). Diarrhea, neutropenia, nausea, vomiting, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, headache, alopecia, thrombocytopenia.
Acalabrutinib (Calquence) (MW 466 g/mol). Anemia, thrombocytopenia, headache, neutropenia, diarrhea, myalgia, bruising.
Avelumab (Bavencio) (MW 147 kg/mol). Fatigue, musculoskeletal pain, diarrhea, nausea, rash, decreased appetite, peripheral edema, urinary tract infection.
Brigatinib (Alunbrig) (MW 584 g/mol). Nausea, fatigue, cough, headache.
Copanlisib (Aliqopa) (MW 480 g/mol). Hyperglycemia, diarrhea, decreased strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory infections, thrombocytopenia.
Durvalumab (Imfinzi) (MW 146 kg/mol). Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infections, cough, upper respiratory tract infections, dyspnea, rash.
Enasidenib mesylate (Idhifa) (MW 569 g/mol). Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite.
Inotuzumab ozogamicin (Besponsa) (MW 160 kg/mol). Thrombocytopenia, neutropenia, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, increased gamma-glutamyltransferase, and hyperbilirubinemia.
Midostaurin (Rydapt) (MW 571 g/mol). Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, vomiting, diarrhea, edema, pyrexia, dyspnea.
Neratinib (Nerlynx) (MW 557 g/mol). Diarrhea, nausea, vomiting, abdominal pain, fatigue, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, nail disorder, dry skin, abdominal distention, decreased weight, urinary tract infection.
Niraparib (Zejula) (MW 511 g/mol). Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, vomiting, constipation, abdominal pain/distention, mucositis/stomatitis, diarrhea, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.
Ribociclib (Kisqali) (MW 553 g/mol). Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046 g/mol). Thromboembolic events.
Central nervous system
Deutetrabenazine (Austedo) (MW 324 g/mol). Somnolence, diarrhea, dry mouth, fatigue, nasopharyngitis.
Edaravone (Radicava) (MW 174 g/mol). Confusion, gait disturbance, headache.
Naldemedine (Symproic) (MW 743 g/mol). Abdominal pain, diarrhea, nausea, gastroenteritis.
Ocrelizumab (Ocrevus) (MW 145 kg/mol). Upper and lower respiratory tract infections.
Safinamide (Xadago) (MW 399 g/mol). Dyskinesia, fall, nausea, insomnia.
Valbenazine (Ingrezza) (MW 419 g/mol). Somnolence.
Dermatologic
Brodalumab (Siliq) (MW 144 kg/mol). Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, influenza, neutropenia, tinea infections.
Dupilumab (Dupixent) (MW 146.9 kg/mol). Conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye.
Guselkumab (Tremfya) (MW 143.6 kg/mol). Upper respiratory infections, headache, arthralgia, diarrhea, gastroenteritis, tinea infections, herpes simplex infections.
Endocrine / metabolic
Deflazacort (Emflaza) (MW 442 g/mol). Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, nasopharyngitis.
Ertugliflozin (Steglatro) (MW 566 g/mol). Female genital mycotic infections.
Etelcalcetide (Parsabiv) (MW 1,048 g/mol). Blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, paresthesia.
Macimorelin (Macrilen) (MW 535 g/mol). Dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, sinus bradycardia.
Semaglutide (Ozempic) (MW 4,114 g/mol). Nausea, vomiting, diarrhea, abdominal pain, constipation.
Vestronidase alfa (Mepsevii) (MW 72.5 kg/mol). Diarrhea, rash, anaphylaxis, pruritus.
Gastrointestinal
Plecanatide (Trulance) (MW 1.7 kg/mol). Diarrhea.
Telotristat (Xermelo) (MW 574 g/mol). Nausea, headache, increased gamma-glutamyltransferase, depression, flatulence, decreased appetite, peripheral edema, pyrexia.
Hematologic
Betrixaban (Bevyxxa) (MW 568 g/mol). Bleeding.
Emicizumab (Hemlibra) (MW 145.6 kg/mol). Headache, arthralgia.
Immunologic
Sarilumab (Kevzara) (MW 150 kg/mol). Neutropenia, increased ALT, upper respiratory infections, urinary tract infections.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508 g/mol). All related to the eye.
Netarsudil (Rhopressa) (MW 454 g/mol). All related to the eye.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3.9 kg/mol). Hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, vertigo.
Respiratory
Benralizumab (Fasenra) (MW 150 kg/mol). Headache, pharyngitis.
A new way to classify endometrial cancer
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
We classify endometrial cancer so that we can communicate and define each patient’s disease status, the potential for harm, and the likelihood that adjuvant therapies might provide help. Traditional forms of classification have clearly fallen short in achieving this aim, as we all know of patients with apparent low-risk disease (such as stage IA grade 1 endometrioid carcinoma) who have had recurrences and died from their disease, and we know that many patients have been subjected to overtreatment for their cancer and have acquired lifelong toxicities of therapy. This column will explore the newer, more sophisticated molecular-based classifications that are being validated for endometrial cancer, and the ways in which this promises to personalize the treatment of endometrial cancer.
Breast cancer and melanoma are examples of the inclusion of molecular data such as hormone receptor status, HER2/neu status, or BRAF positivity resulting in advancements in personalizing therapeutics. We are now moving toward this for endometrial cancer.
What is the Cancer Genome Atlas?
In 2006 the National Institutes of Health announced an initiative to coordinate work between the National Cancer Institute and the National Human Genome Research Institute taking information about the human genome and analyzing it for key genomic alterations found in 33 common cancers. These data were combined with clinical information (such as survival) to classify the behaviors of those cancers with respect to their individual genomic alternations, in order to look for patterns in mutations and behaviors. The goal of this analysis was to shift the paradigm of cancer classification from being centered around primary organ site toward tumors’ shared genomic patterns.
In 2013 the Cancer Genome Atlas published their results of complete gene sequencing in endometrial cancer.3 The authors identified four discrete subgroups of endometrial cancer with distinct molecular mutational profiles and distinct clinical outcomes: polymerase epsilon (POLE, pronounced “pole-ee”) ultramutated, microsatellite instability (MSI) high, copy number high, and copy number low.
POLE ultramutated
An important subgroup identified in the Cancer Genome Atlas was a group of patients with a POLE ultramutated state. POLE encodes for a subunit of DNA polymerase, the enzyme responsible for replicating the leading DNA strand. Nonfunctioning POLE results in proofreading errors and a subsequent ultramutated cellular state with a predominance of single nucleotide variants. POLE proofreading domain mutations in endometrial cancer and colon cancer are associated with excellent prognosis, likely secondary to the immune response that is elicited by this ultramutated state from creation of “antigenic neoepitopes” that stimulate T-cell response. Effectively, the very mutated cell is seen as “more foreign” to the body’s immune system.
Approximately 10% of patients with endometrial cancer have a POLE ultramutated state, and, as stated above, prognosis is excellent, even if coexisting with a histologic cell type (such as serous) that is normally associated with adverse outcomes. These women tend to be younger, with a lower body mass index, higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and low stage.
MSI high
MSI (microsatellite instability) is a result of epigenetic/hypermethylations or loss of expression in mismatch repair genes (such as MLH1, MSH2, MSH6, PMS2). These genes code for proteins critical in the repair of mismatches in short repeated sequences of DNA. Loss of their function results in an accumulation of errors in these sequences: MSI. It is a feature of the Lynch syndrome inherited state, but is also found sporadically in endometrial tumors. These tumors accumulate a number of mutations during cell replication that, as in POLE hypermutated tumors, are associated with eliciting an immune response.
These tumors tend to be associated with a higher-grade endometrioid cell type, the presence of lymphovascular space invasion, and an advanced stage. Patients with tumors that have been described as MSI high are candidates for “immune therapy” with the PDL1 inhibitor pembrolizumab because of their proinflammatory state and observed favorable responses in clinical trials.4
Copy number high/low
Copy number (CN) high and low refers to the results of microarrays in which hierarchical clustering was applied to identify reoccurring amplification or deletion regions. The CN-high group was associated with the poorest outcomes (recurrence and survival). There is significant overlap with mutations in TP53. Most serous carcinomas were CN high; however, 25% of patients with high-grade endometrioid cell type shared the CN-high classification. These tumors shared great molecular similarity to high-grade serous ovarian cancers and basal-like breast cancer.
Those patients who did not possess mutations that classified them as POLE hypermutated, MSI high, or CN high were classified as CN low. This group included predominantly grades 1 and 2 endometrioid adenocarcinomas of an early stage and had a favorable prognostic profile, though less favorable than those with a POLE ultramutated state, which appears to be somewhat protective.
Molecular/metabolic interactions
While molecular data are clearly important in driving a cancer cell’s behavior, other clinical and metabolic factors influence cancer behavior. For example, body mass index, adiposity, glucose, and lipid metabolism have been shown to be important drivers of cellular behavior and responsiveness to targeted therapies.5,6 Additionally age, race, and other metabolic states contribute to oncologic behavior. Future classifications of endometrial cancer are unlikely to use molecular profiles in isolation but will need to incorporate these additional patient-specific data to better predict and prognosticate outcomes.
Clinical applications
If researchers can better define and describe a patient’s endometrial cancer from the time of their biopsy, important clinical decisions might be able to be tackled. For example, in a premenopausal patient with an endometrial cancer who is considering fertility-sparing treatments, preoperative knowledge of a POLE ultramutated state (and therefore an anticipated good prognosis) might favor fertility preservation or avoid comprehensive staging which may be of limited value. Similarly, if an MSI-high profile is identified leading to a Lynch syndrome diagnosis, she may be more inclined to undergo a hysterectomy with bilateral salpingo-oophorectomy and staging as she is at known increased risk for a more advanced endometrial cancer, as well as the potential for ovarian cancer.
Postoperative incorporation of molecular data promises to be particularly helpful in guiding adjuvant therapies and sparing some women from unnecessary treatments. For example, women with high-grade endometrioid tumors who are CN high were historically treated with radiotherapy but might do better treated with systemic adjuvant therapies traditionally reserved for nonendometrioid carcinomas. Costly therapies such as immunotherapy can be directed toward those with MSI-high tumors, and the rare patient with a POLE ultramutated state who has a recurrence or advanced disease. Clinical trials will be able to cluster enrollment of patients with CN-high, serouslike cancers with those with serous cancers, rather than combining them with patients whose cancers predictably behave much differently.
Much work is still needed to validate this molecular profiling in endometrial cancer and define the algorithms associated with treatment decisions; however, it is likely that the way we describe endometrial cancer in the near future will be quite different.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no disclosures.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-7.
2. Clarke BA et al. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63(5):410-5.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
4. Ott PA et al. Pembrolizumab in advanced endometrial cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):Abstract 5581.
5. Roque DR et al. Association between differential gene expression and body mass index among endometrial cancers from the Cancer Genome Atlas Project. Gynecol Oncol. 2016;142(2):317-22.
6. Talhouk A et al. New classification of endometrial cancers: The development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract. 2016 Dec;3:14.
Sexual harassment and medicine
Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?
In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.1 The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.
Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.2 But what about medicine? To answer this question, this article aims to:
- review the dilemma
- explore our duty to our patients and each other
- discuss solutions to address the problem.
Sexual harassment: A brief history
Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.3
The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.
Continue to: That was until an FBI interview...
That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.4 Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.
Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.5
A forensic assessment of harassment
Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.6 Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”
The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.7 This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:
Meritor Savings Bank, FSB v Vinson (1986).8 This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.
Continue to: Harris v Forklift Systems, Inc. (1993)
Harris v Forklift Systems, Inc. (1993).9 Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.
Physicians are not immune
Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.10
But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.11
A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.12 In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.12
Continue to: But what about the progress women have made...
But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.13 Yet there has been a stalling in terms of change when it comes to harassment.12 Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.
Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.11 Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.
The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.14
Time for action
The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.
Continue to: One way to change any culture...
One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.17
Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.17
Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.18 All institutions should encourage reporting along confidential pathways and have multiple ways to report.17 Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.
Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.17
Continue to: Although this article focuses...
Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.
The task ahead is large, and this discussion is not over.
1. Felsenthal E. TIME’s 2017 Person of the Year: the Silence Breakers. TIME. http://time.com/magazine/us/5055335/december-18th-2017-vol-190-no-25-u-s/. Published December 18, 2017. Accessed April 23, 2018.
2. Hiltzik M. Los Angeles Times. Will medicine be the next field to face a sexual harassment reckoning? http://www.latimes.com/business/hiltzik/la-fi-hiltzik-medicine-harassment-20180110-story.html. Published January 10, 2018. Accessed April 23, 2018.
3. Thompson K. For Anita Hill, the Clarence Thomas hearings haven’t really ended. The Washington Post. https://www.washingtonpost.com/politics/for-anita-hill-the-clarence-thomas-hearings-havent-really-ended/2011/10/05/gIQAy2b5QL_story.html. Published October 6, 2011. Accessed April 23, 2018.
4. Toobin J. Good versus evil. In: Toobin J. The nine: inside the secret world of the Supreme Court. New York, NY: Doubleday; 2007:30-32.
5. Barnes B. Motion picture academy finds no merit to accusations against its president. https://www.nytimes.com/2018/03/28/business/media/john-bailey-sexual-harassment-academy.html. The New York Times. Published March 28, 2018. Accessed April 23, 2018.
6. Thomas G. Because of sex: one law, ten cases, and fifty years that changed American women’s lives at work. New York, NY: Picador; 2016.
7. Landmark cases 2014. American Academy of Psychiatry and Law. http://www.aapl.org/landmark_list.htm. 2014. Accessed April 22, 2018.
8. Meritor Savings Bank v Vinson, 477 US 57 (1986).
9. Harris v Forklift Systems, Inc., 114 S Ct 367 (1993).
10. Okwerekwu JA. #MeToo: so many of my patients have a story. And absorbing them is taking its toll. STAT. https://www.scribd.com/article/367482959/Me-Too-So-Many-Of-My-Patients-Have-A-Story-And-Absorbing-Them-Is-Taking-Its-Toll. Published December 18, 2017. Accessed April 23, 2018.
11. Jagsi R. Sexual harassment in medicine—#MeToo. N Engl J Med. 2018;378:209-211.
12. Jagsi R, Griffith KA, Jones R. et al. Sexual harassment and discrimination experiences of academic medical faculty. JAMA. 2016;315(19):2120-2121.
13. AAMCNEWS. More women than men enrolled in U.S. medical schools in 2017. https://news.aamc.org/press-releases/article/applicant-enrollment-2017/. Published December 18, 2017. Accessed May 4, 2018.
14. Miller D. #MeToo: does it help? Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/150148/depression/metoo-does-it-help. Published October 24, 2017. Accessed April 23, 2018.
15. Chang S, Morahan PS, Magrane D, et al. Retaining faculty in academic medicine: the impact of career development programs for women. J Womens Health (Larchmt). 2016;25(7):687-696.
16. Lautenberger DM, Dandar, VM, Raezer CL, et al. The state of women in academic medicine: the pipeline and pathways to leadership, 2013-2014. AAMC. https://members.aamc.org/eweb/upload/The%20State%20of%20Women%20in%20Academic%20Medicine%202013-2014%20FINAL.pdf. Published 2014. Accessed May 4, 2018.
17. Jablow M. Zero tolerance: combating sexual harassment in academic medicine. AAMCNews. https://news.aamc.org/diversity/article/combating-sexual-harassment-academic-medicine. Published April 4, 2017. Accessed April 23, 2018.
18. University of Wisconsin-Madison, the School of Medicine and Public Health. UW-Madison Policy on Sexual Harassment and Sexual Violence. https://compliance.wiscweb.wisc.edu/wp-content/uploads/sites/102/2018/01/UW-Madison-Policy-on-Sexual-Harassment-And-Sexual-Violence-January-2018.pdf. Published January 2018. Accessed April 22, 2018.
Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?
In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.1 The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.
Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.2 But what about medicine? To answer this question, this article aims to:
- review the dilemma
- explore our duty to our patients and each other
- discuss solutions to address the problem.
Sexual harassment: A brief history
Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.3
The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.
Continue to: That was until an FBI interview...
That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.4 Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.
Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.5
A forensic assessment of harassment
Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.6 Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”
The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.7 This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:
Meritor Savings Bank, FSB v Vinson (1986).8 This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.
Continue to: Harris v Forklift Systems, Inc. (1993)
Harris v Forklift Systems, Inc. (1993).9 Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.
Physicians are not immune
Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.10
But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.11
A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.12 In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.12
Continue to: But what about the progress women have made...
But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.13 Yet there has been a stalling in terms of change when it comes to harassment.12 Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.
Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.11 Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.
The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.14
Time for action
The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.
Continue to: One way to change any culture...
One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.17
Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.17
Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.18 All institutions should encourage reporting along confidential pathways and have multiple ways to report.17 Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.
Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.17
Continue to: Although this article focuses...
Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.
The task ahead is large, and this discussion is not over.
Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?
In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.1 The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.
Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.2 But what about medicine? To answer this question, this article aims to:
- review the dilemma
- explore our duty to our patients and each other
- discuss solutions to address the problem.
Sexual harassment: A brief history
Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.3
The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.
Continue to: That was until an FBI interview...
That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.4 Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.
Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.5
A forensic assessment of harassment
Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.6 Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”
The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.7 This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:
Meritor Savings Bank, FSB v Vinson (1986).8 This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.
Continue to: Harris v Forklift Systems, Inc. (1993)
Harris v Forklift Systems, Inc. (1993).9 Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.
Physicians are not immune
Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.10
But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.11
A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.12 In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.12
Continue to: But what about the progress women have made...
But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.13 Yet there has been a stalling in terms of change when it comes to harassment.12 Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.
Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.11 Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.
The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.14
Time for action
The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.
Continue to: One way to change any culture...
One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.17
Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.17
Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.18 All institutions should encourage reporting along confidential pathways and have multiple ways to report.17 Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.
Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.17
Continue to: Although this article focuses...
Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.
The task ahead is large, and this discussion is not over.
1. Felsenthal E. TIME’s 2017 Person of the Year: the Silence Breakers. TIME. http://time.com/magazine/us/5055335/december-18th-2017-vol-190-no-25-u-s/. Published December 18, 2017. Accessed April 23, 2018.
2. Hiltzik M. Los Angeles Times. Will medicine be the next field to face a sexual harassment reckoning? http://www.latimes.com/business/hiltzik/la-fi-hiltzik-medicine-harassment-20180110-story.html. Published January 10, 2018. Accessed April 23, 2018.
3. Thompson K. For Anita Hill, the Clarence Thomas hearings haven’t really ended. The Washington Post. https://www.washingtonpost.com/politics/for-anita-hill-the-clarence-thomas-hearings-havent-really-ended/2011/10/05/gIQAy2b5QL_story.html. Published October 6, 2011. Accessed April 23, 2018.
4. Toobin J. Good versus evil. In: Toobin J. The nine: inside the secret world of the Supreme Court. New York, NY: Doubleday; 2007:30-32.
5. Barnes B. Motion picture academy finds no merit to accusations against its president. https://www.nytimes.com/2018/03/28/business/media/john-bailey-sexual-harassment-academy.html. The New York Times. Published March 28, 2018. Accessed April 23, 2018.
6. Thomas G. Because of sex: one law, ten cases, and fifty years that changed American women’s lives at work. New York, NY: Picador; 2016.
7. Landmark cases 2014. American Academy of Psychiatry and Law. http://www.aapl.org/landmark_list.htm. 2014. Accessed April 22, 2018.
8. Meritor Savings Bank v Vinson, 477 US 57 (1986).
9. Harris v Forklift Systems, Inc., 114 S Ct 367 (1993).
10. Okwerekwu JA. #MeToo: so many of my patients have a story. And absorbing them is taking its toll. STAT. https://www.scribd.com/article/367482959/Me-Too-So-Many-Of-My-Patients-Have-A-Story-And-Absorbing-Them-Is-Taking-Its-Toll. Published December 18, 2017. Accessed April 23, 2018.
11. Jagsi R. Sexual harassment in medicine—#MeToo. N Engl J Med. 2018;378:209-211.
12. Jagsi R, Griffith KA, Jones R. et al. Sexual harassment and discrimination experiences of academic medical faculty. JAMA. 2016;315(19):2120-2121.
13. AAMCNEWS. More women than men enrolled in U.S. medical schools in 2017. https://news.aamc.org/press-releases/article/applicant-enrollment-2017/. Published December 18, 2017. Accessed May 4, 2018.
14. Miller D. #MeToo: does it help? Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/150148/depression/metoo-does-it-help. Published October 24, 2017. Accessed April 23, 2018.
15. Chang S, Morahan PS, Magrane D, et al. Retaining faculty in academic medicine: the impact of career development programs for women. J Womens Health (Larchmt). 2016;25(7):687-696.
16. Lautenberger DM, Dandar, VM, Raezer CL, et al. The state of women in academic medicine: the pipeline and pathways to leadership, 2013-2014. AAMC. https://members.aamc.org/eweb/upload/The%20State%20of%20Women%20in%20Academic%20Medicine%202013-2014%20FINAL.pdf. Published 2014. Accessed May 4, 2018.
17. Jablow M. Zero tolerance: combating sexual harassment in academic medicine. AAMCNews. https://news.aamc.org/diversity/article/combating-sexual-harassment-academic-medicine. Published April 4, 2017. Accessed April 23, 2018.
18. University of Wisconsin-Madison, the School of Medicine and Public Health. UW-Madison Policy on Sexual Harassment and Sexual Violence. https://compliance.wiscweb.wisc.edu/wp-content/uploads/sites/102/2018/01/UW-Madison-Policy-on-Sexual-Harassment-And-Sexual-Violence-January-2018.pdf. Published January 2018. Accessed April 22, 2018.
1. Felsenthal E. TIME’s 2017 Person of the Year: the Silence Breakers. TIME. http://time.com/magazine/us/5055335/december-18th-2017-vol-190-no-25-u-s/. Published December 18, 2017. Accessed April 23, 2018.
2. Hiltzik M. Los Angeles Times. Will medicine be the next field to face a sexual harassment reckoning? http://www.latimes.com/business/hiltzik/la-fi-hiltzik-medicine-harassment-20180110-story.html. Published January 10, 2018. Accessed April 23, 2018.
3. Thompson K. For Anita Hill, the Clarence Thomas hearings haven’t really ended. The Washington Post. https://www.washingtonpost.com/politics/for-anita-hill-the-clarence-thomas-hearings-havent-really-ended/2011/10/05/gIQAy2b5QL_story.html. Published October 6, 2011. Accessed April 23, 2018.
4. Toobin J. Good versus evil. In: Toobin J. The nine: inside the secret world of the Supreme Court. New York, NY: Doubleday; 2007:30-32.
5. Barnes B. Motion picture academy finds no merit to accusations against its president. https://www.nytimes.com/2018/03/28/business/media/john-bailey-sexual-harassment-academy.html. The New York Times. Published March 28, 2018. Accessed April 23, 2018.
6. Thomas G. Because of sex: one law, ten cases, and fifty years that changed American women’s lives at work. New York, NY: Picador; 2016.
7. Landmark cases 2014. American Academy of Psychiatry and Law. http://www.aapl.org/landmark_list.htm. 2014. Accessed April 22, 2018.
8. Meritor Savings Bank v Vinson, 477 US 57 (1986).
9. Harris v Forklift Systems, Inc., 114 S Ct 367 (1993).
10. Okwerekwu JA. #MeToo: so many of my patients have a story. And absorbing them is taking its toll. STAT. https://www.scribd.com/article/367482959/Me-Too-So-Many-Of-My-Patients-Have-A-Story-And-Absorbing-Them-Is-Taking-Its-Toll. Published December 18, 2017. Accessed April 23, 2018.
11. Jagsi R. Sexual harassment in medicine—#MeToo. N Engl J Med. 2018;378:209-211.
12. Jagsi R, Griffith KA, Jones R. et al. Sexual harassment and discrimination experiences of academic medical faculty. JAMA. 2016;315(19):2120-2121.
13. AAMCNEWS. More women than men enrolled in U.S. medical schools in 2017. https://news.aamc.org/press-releases/article/applicant-enrollment-2017/. Published December 18, 2017. Accessed May 4, 2018.
14. Miller D. #MeToo: does it help? Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/150148/depression/metoo-does-it-help. Published October 24, 2017. Accessed April 23, 2018.
15. Chang S, Morahan PS, Magrane D, et al. Retaining faculty in academic medicine: the impact of career development programs for women. J Womens Health (Larchmt). 2016;25(7):687-696.
16. Lautenberger DM, Dandar, VM, Raezer CL, et al. The state of women in academic medicine: the pipeline and pathways to leadership, 2013-2014. AAMC. https://members.aamc.org/eweb/upload/The%20State%20of%20Women%20in%20Academic%20Medicine%202013-2014%20FINAL.pdf. Published 2014. Accessed May 4, 2018.
17. Jablow M. Zero tolerance: combating sexual harassment in academic medicine. AAMCNews. https://news.aamc.org/diversity/article/combating-sexual-harassment-academic-medicine. Published April 4, 2017. Accessed April 23, 2018.
18. University of Wisconsin-Madison, the School of Medicine and Public Health. UW-Madison Policy on Sexual Harassment and Sexual Violence. https://compliance.wiscweb.wisc.edu/wp-content/uploads/sites/102/2018/01/UW-Madison-Policy-on-Sexual-Harassment-And-Sexual-Violence-January-2018.pdf. Published January 2018. Accessed April 22, 2018.
Is anatomy destiny? Not according to GxE!
The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.1,2 This is as true for psychiatric brain disorders as for any other medical illness.
The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.
Consider the following examples of how genes are not the sole determinants of one’s mental health:
- A landmark study conducted in New Zealand3 followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
- In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.4 They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
- Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.5 Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
- A recent study6 identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
- A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.
The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.
1. Ridley M. Nature via nurture: genes, experience and what makes us human. New York, NY: Harper Collins; 2003.
2. Rutter M. Genes and behavior: nature–nurture interplay explained. Malden, MA: Blackwell Publishing; 2006.
3. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
4. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Science. 2002;297(5582):851-854.
5. Stabenau JR, Pollin W. Heredity and environment in schizophrenia, revisited. The contribution of twin and high-risk studies. J Nerv Ment Dis. 1993;181(5):290-297.
6. Nishioka M, Bundo M, Ueda J, et al. Identification of somatic mutations in monozygotic twins discordant for psychiatric disorders. NPJ Schizophr. 2018;4(1):7.
The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.1,2 This is as true for psychiatric brain disorders as for any other medical illness.
The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.
Consider the following examples of how genes are not the sole determinants of one’s mental health:
- A landmark study conducted in New Zealand3 followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
- In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.4 They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
- Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.5 Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
- A recent study6 identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
- A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.
The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.
The long-held dogma that “anatomy is destiny” is fraying at the edges. The traditional nature vs nurture debate has also undergone a major transformation into a gene-by-environment interaction, abbreviated as GxE in the medical literature.1,2 This is as true for psychiatric brain disorders as for any other medical illness.
The pessimistic determinism of “anatomy is destiny” has given way to a much more optimistic perspective, especially for the most plastic of all organs, the human brain. While genes are essential to construct one’s anatomy, environmental factors can significantly modulate gene expression. A person’s life experiences, good or bad, can wield a lasting influence on one’s brain structure and function, often transcending what is coded by the genome. For the mind, its thoughts, emotions, and cognition, the neurogenetic “tyranny” can be curbed or modified by one’s experiences. This epigenetic process is alive and well and known to be mediated by DNA methylation and histone modifications.
Consider the following examples of how genes are not the sole determinants of one’s mental health:
- A landmark study conducted in New Zealand3 followed a cohort of 847 individuals from age 3 to 26. Researchers recorded stressful life events for each participant, including romantic breakups, grief, medical illness, or employment problems, between age 21 and 26. Participants were evaluated for depressive episodes and hospitalizations and their genes tested for whether each individual carried the short (S) or long (L) allele of the serotonin transporter (5-HTT) gene. They found that when life stresses occurred, the probability of depression was much higher among the subgroup who were SS homozygous than among the LL homozygous subgroup. Thus, the genetic vulnerability to depression did not manifest itself unless adverse environmental events occurred. This is a classic example of GxE interaction, where genes alone are insufficient to produce a psychiatric disorder without environmental events interacting with them and triggering the psychopathology.
- In the same cohort described above, investigators showed that some children who were abused at an early age developed antisocial behavior as adults, while others did not.4 They discovered that a high expression of a polymorphism in the gene that codes for monoamine oxidase A had a protective effect that decreased the likelihood of developing antisocial traits in children who experienced trauma. In this case, the life experience failed to worsen a child’s behavior in the presence of elevated levels of a genetically determined protective enzyme.
- Schizophrenia is a heterogeneous neurodevelopmental syndrome caused by numerous genetic factors (risk genes, copy number variants, and de novo mutations) and a wide variety of perinatal complications. Concordance for schizophrenia in monozygotic twins who have identical genes is only 50%, not 100% as would be expected.5 Obviously, nongenetic factors during fetal life must play a role in disrupting the neurodevelopment of the affected twin, but not in the healthy twin. Examples of such factors may include differential distribution of blood during fetal life, leading to low birthweight and hypoplastic brain volume in the affected twin. It may also be due to labor complications, where one twin has an uneventful vaginal delivery while the other experiences hypoxia, a brain insult, due to a complicated breech delivery. Thus, despite having the same genes, the postnatal outcome in a discordant monozygotic twin pair diverges dramatically.
- A recent study6 identified somatic mutations in monozygotic twins discordant for psychiatric disorders, including schizophrenia and delusional disorder. Such somatic mutations have also been found in Van der Woude syndrome, which includes cleft palate. However, skillful surgeons can repair the cleft palate and allow the affected twin to have a normal facial appearance and oral functions, offsetting the abnormal genetic code.
- A monozygotic twin pair (one of whom was a patient of mine) born to a mother with bipolar disorder and adopted at birth by different families developed bipolar disorder due to genetic transmission, but eventually had very different outcomes. One twin was promptly and successfully treated with lithium at the first manic episode and became a successful teacher and author, while his twin did not receive treatment, became addicted to drugs, was repeatedly incarcerated for assaultive behavior, and later completed suicide at a young age. The appropriate environment and experiences of a person who inherits a psychiatric disorder can dramatically alter the prognosis for the better.
The GxE neurobiological equation is a central feature in many of our patients. As clinicians, we can modulate the patient’s environment by providing timely therapeutic biopsychosocial interventions to our patient to catalyze the GxE equation and veer it towards health, resilience, and wellness. Psychiatric practice can effectively help our patients overcome their genetically and neurobiologically driven maladaptive behavior and enable them to recover from the ravages of neuropsychiatric illness. Thus, psychiatric care represents the ultimate “E” that can interact with and modulate the “G” and effectively demonstrate that anatomy is not destiny.
1. Ridley M. Nature via nurture: genes, experience and what makes us human. New York, NY: Harper Collins; 2003.
2. Rutter M. Genes and behavior: nature–nurture interplay explained. Malden, MA: Blackwell Publishing; 2006.
3. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
4. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Science. 2002;297(5582):851-854.
5. Stabenau JR, Pollin W. Heredity and environment in schizophrenia, revisited. The contribution of twin and high-risk studies. J Nerv Ment Dis. 1993;181(5):290-297.
6. Nishioka M, Bundo M, Ueda J, et al. Identification of somatic mutations in monozygotic twins discordant for psychiatric disorders. NPJ Schizophr. 2018;4(1):7.
1. Ridley M. Nature via nurture: genes, experience and what makes us human. New York, NY: Harper Collins; 2003.
2. Rutter M. Genes and behavior: nature–nurture interplay explained. Malden, MA: Blackwell Publishing; 2006.
3. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
4. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Science. 2002;297(5582):851-854.
5. Stabenau JR, Pollin W. Heredity and environment in schizophrenia, revisited. The contribution of twin and high-risk studies. J Nerv Ment Dis. 1993;181(5):290-297.
6. Nishioka M, Bundo M, Ueda J, et al. Identification of somatic mutations in monozygotic twins discordant for psychiatric disorders. NPJ Schizophr. 2018;4(1):7.
The FDA’s novel drugs approved in 2017
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Novel drugs are innovative new products that have never before been used in clinical practice. Among the 46 that the Food and Drug Administration approved in 2017, 45 could be used in pregnancy. One, cerliponase alfa (Brineura), is indicated for pediatric patients 3 years of age or older, for treatment of late infantile neuronal ceroid lipofuscinosis type 2. It is doubtful that this drug would be used in pregnancy or during breastfeeding.
With the two exceptions noted below, there are no human pregnancy data for these drugs. It is important to consider that although high molecular weight (MW) drugs (for example, greater than 1,000) probably do not usually cross the placenta in the first half of pregnancy, they may do so in late pregnancy. The cited MWs are shown as the nearest whole number. Animal reproductive data are also cited because, although not definitive, they can provide some measure of the human embryo-fetal risk.
Anti-infectives
Benznidazole (same trade name) (MW 441), given orally, is indicated for pediatric patients aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi. However, there are international reports describing its use in pregnancy and breastfeeding. No fetal harm from these exposures were noted. Nevertheless, because of the low MW and the reported animal risk, avoiding the drug during the first half of pregnancy appears to be the best choice. Delafloxacin (Baxdela) (MW 441), a fluoroquinolone antimicrobial given intravenously or orally, is indicated for acute bacterial skin infections. The animal data suggest low risk. However, like other fluoroquinolones, it is contraindicated in pregnancy and should be used only if there are no other alternatives.
Sofosbuvir/velpatasvir /voxilaprevir (Vosevi) (MWs 529, 883, 869), a fixed oral dose combination of three antivirals, is indicated for the treatment of hepatitis C virus infection. The MWs suggest that all three will cross the human placenta. The animal data suggest low risk. Secnidazole (Solosec) (MW 185), given orally, is indicated for the treatment of bacterial vaginosis. It is closely related to metronidazole. No evidence of embryo-fetal toxicity was observed in rats and rabbits, suggesting that the human risk is low. In a report from Brazil, 134 pregnant women with bacterial vaginosis were treated with secnidazole, metronidazole, or tinidazole in the second and third trimesters. Treatment significantly decreased the incidence of premature rupture of membranes, preterm labor, preterm birth, and low birth weight. No fetal harm was reported.
Antineoplastics
[Note: All of the drugs in this category are best avoided, if possible, in pregnancy and breastfeeding.]
Abemaciclib (Verzenio) (MW 507), an oral inhibitor of cyclin-dependent kinases, is indicated for the treatment of breast cancer. The drug is teratogenic in rats. Acalabrutinib (Calquence) (MW 466) is an oral kinase inhibitor indicated for mantle cell lymphoma. The drug had no effect on the rat embryo-fetus but caused decreased fetal body weights and delayed skeletal ossification in rabbits. Avelumab (Bavencio) (MW 147,000) is given intravenously for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma. Animal reproduction studies have not been conducted. However, based on its mechanism of action, fetal exposure may increase the risk of developing immune-related disorders or altering the normal immune response.
Brigatinib (Alunbrig) (MW 584) is given orally for the treatment of metastatic non–small-cell lung cancer. In rats, doses less than or slightly above the human exposure caused multiple anomalies in the fetuses of pregnant rats. Copanlisib (Aliqopa) (MW 553) is a kinase inhibitor that is given intravenously for relapsed follicular lymphoma. In rats during organogenesis, doses based on body surface area that were a fraction of the human dose caused embryo-fetal death and fetal defects. Durvalumab (Imfinzi) (MW 146,000), given intravenously, is indicated for the treatment of metastatic urothelial carcinoma and non–small-cell lung cancer. Monkeys given the drug from organogenesis through delivery experienced increased premature birth, fetal loss, and premature neonatal death. Women of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
Enasidenib (Idhifa) (MW 569), given orally, is indicated for the treatment of myeloid leukemia. The drug caused maternal toxicity and adverse embryo-fetal effects (postimplantation loss, resorptions, decrease viable fetuses, lower fetal birth weights, and skeletal variations) in rats and spontaneous abortions in rabbits. Inotuzumab ozogamicin (Besponsa) (MW 160,000), given intravenously, is indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug caused fetal harm in rats but not in rabbits. Midostaurin (Rydapt) (MW 571) is an oral kinase inhibitor indicated for myeloid leukemia. In rats, a dose given during the first week of pregnancy that was a small fraction of the human exposure caused pre- and postimplantation loss. When very small doses were given during organogenesis to rats and rabbits there was significant maternal and fetal toxicity.
Neratinib (Nerlynx) (MW 673) is an oral kinase inhibitor for breast cancer. Although the drug did not cause embryo-fetal toxicity in rats, it did cause this toxicity in rabbits. Doses that resulted in exposures that were less than the human exposure caused maternal toxicity, abortions, and embryo-fetal death. Lower doses caused multiple fetal anomalies. Niraparib (Zejula) (MW 511) is indicated for treatment of epithelial ovarian, fallopian, or peritoneal cancer. Because of the potential human embryo-fetal risk based on its mechanism of action, pregnant animal studies were not conducted. Women with reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Ribociclib (Kisqali) (MW 553) is an oral kinase inhibitor indicated for postmenopausal women with breast cancer. In rats, the drug cause reduced fetal weights and skeletal changes. Increased incidences of fetal abnormalities and lower fetal weights were observed in rabbits.
Cardiovascular
Angiotensin II (Giapreza) (MW 1,046) is a naturally occurring peptide hormone given as an intravenous infusion. It is indicated as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. Animal reproduction studies have not been conducted. Because septic or other distributive shock is a medical emergency that can be fatal, the use of this agent in pregnancy should not be withheld.
Central nervous system
Deutetrabenazine (Austedo) (MW 324) is an oral drug indicated for the treatment of chorea associated with Huntington’s disease and for tardive dyskinesia. When given to rats during organogenesis there was no clear effect on embryo-fetal development.
Edaravone (Radicava) (MW 174), given as an intravenous infusion, is indicated for the treatment of amyotrophic lateral sclerosis. Doses that were not maternal toxic did not cause embryo-fetal toxicity in rats and rabbits. However, the no-effect dose for developmental toxicity was less than the recommended human dose. Naldemedine (Symproic) (MW 743) is an opioid antagonist indicated for the treatment of opioid-induced constipation. The drug crosses the human placenta and may precipitate opioid withdrawal in the fetus. The drug caused no embryo-fetal adverse effects, even at high doses, in pregnant rats and rabbits.
Ocrelizumab (Ocrevus) (MW 145,000), an intravenous agent, is used to treat patients with multiple sclerosis. The MW is high but immunoglobulins are known to cross the placenta. When given to monkeys at doses similar to or greater than the human dose, there was increased perinatal mortality, depletion of B-cell populations, and renal, bone marrow, and testicular toxicity in the offspring in the absence of maternal toxicity. Safinamide (Xadago) (MW 399) is an oral drug indicated as adjunctive treatment to levodopa/carbidopa in Parkinson’s disease. In rats, the drug was teratogenic (mainly urogenital defects) at all doses. When it was combined with levodopa/carbidopa or used alone, increased rates of fetal visceral and skeletal defects occurred at all doses studied. In rabbits, given the combination throughout organogenesis, there was an increased incidence of embryo-fetal death and cardiac and skeletal defects. Based on these data, avoiding the drug in pregnancy appears to be the best course.
Valbenazine (Ingrezza) (MW 419) is indicated for the treatment of tardive dyskinesia. The drug caused no malformations in rats and rabbits. However, in rats given the drug during organogenesis through lactation, an increase in the number of stillborn pups and postnatal pup mortalities was observed.
Dermatologic
Brodalumab (Siliq) (MW 144,000), given subcutaneously, is indicated for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In monkeys, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from mothers given weekly subcutaneous doses of the drug. Dupilumab (Dupixent) (MW 144,000) is given subcutaneously for the treatment of atopic dermatitis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age.
Guselkumab (Tremfya) (MW 143,600) is given subcutaneously for the treatment of moderate to severe plaque psoriasis. It is a human monoclonal IgG antibody and, even though the MW is high, IgG antibodies are known to cross the placenta. In pregnant monkeys given subcutaneous doses of the drug, no drug-related effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from birth to 6 months of age. However, neonatal deaths were observed in three monkeys given six times the maximum recommended human dose.
Endocrine/metabolic
Deflazacort (Emflaza) (MW 442) is an oral corticosteroid prodrug indicated for the treatment of Duchenne muscular dystrophy. The drug is converted in vivo to an active metabolite. The drug readily crosses the placenta. Although animal reproduction studies have not been conducted, such studies with other corticosteroids in various animal species have shown an increased incidence of cleft palate. In some species, there was an increase in embryo-fetal death, intrauterine growth restriction, and constriction of the ductus arteriosus.
Ertugliflozin (Steglatro) (MW 566) is an oral drug indicated to improve glycemic control in adults with type 2 diabetes mellitus. In juvenile rats, doses that were about 13 times the human dose caused increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization. These effects occurred during periods of rat renal development that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period. Etelcalcetide (Parsabiv) (MW 1,048), an intravenous calcium-sensing receptor agonist, is indicated for patients on hemodialysis who have secondary hyperparathyroidism. In rats and rabbits given the drug during organogenesis, there was reduced fetal growth. In rats given the drug during organogenesis through birth and weaning, there was a slight increase in pup mortality, delay in parturition, and transient effects on pup growth, but there were no effects on sexual maturation, neurobehavioral, or reproductive function. Macimorelin (Macrilen) (MW 535) is an oral growth hormone secretagogue receptor agonist. It is indicated for adult growth hormone deficiency. Animal reproduction studies have not been conducted.
Semaglutide (Ozempic) (MW 4,114), given subcutaneously, is a glucagon-like peptide indicated to improve glycemic control in type 2 diabetes mellitus. In rats given the drug during organogenesis, embryo-fetal death, structural defects, and alterations in growth were observed. In rabbits and monkeys given the drug during organogenesis, there were early pregnancy losses and structural abnormalities. In addition, there was marked maternal body weight loss in both animal species. Vestronidase alfa-vjbk (Mepsevii) is given intravenously. It is indicated for the treatment of Mucopolysaccharidosis VII (Sly syndrome). The calculated average MW of each nonglycosylated peptide chain is 72,562. In rats and rabbits given the drug during organogenesis, there was no maternal toxicity or adverse developmental outcomes.
Gastrointestinal
Plecanatide (Trulance) (MW 1,682) is an oral drug indicated for the treatment of constipation. The drug and its active metabolite are negligibly absorbed systemically and fetal exposure to the drug is not expected. In mice and rabbits given the oral drug during organogenesis, no effects on embryo-fetal development were observed. Telotristat ethyl (Xermelo) (MW 754) is an oral drug indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (MW not specified) therapy in adults not controlled by somatostatin analog. When given during organogenesis in rats, there was no effect on embryo-fetal development at doses that were about nine times the recommended human dose. However, an increased incidence of mortality in rat offspring was observed when the drug was given from organogenesis through lactation. During organogenesis in rabbits, the drug had no embryo-fetal effects at doses that were 10 or more times the human dose.
Hematologics
Betrixaban (Bevyxxa) (MW 568) is an oral factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism. The drug was not associated with adverse developmental fetal outcomes in rats and rabbits. However, maternal hemorrhage did occur. In humans, there is an increased risk of hemorrhage during pregnancy and delivery. Emicizumab (Hemlibra) (MW 145,600), given subcutaneously, is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding in patients with hemophilia A with factor VIII inhibitors. Animal reproduction studies have not been conducted. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta.
Immunologic
Sarilumab (Kevzara) (MW 150,000) is given subcutaneously. It is indicated for patients with moderate to severe rheumatoid arthritis. Reproduction studies were conducted in pregnant monkeys. There was no evidence of embryo toxicity or fetal malformations. Based on this data, the human pregnancy risk is low.
Ophthalmic
Latanoprostene bunod (Vyzulta) (MW 508) is a prostaglandin analog that is indicated to reduce intraocular pressure. No quantifiable plasma concentrations of latanoprostene bunod were detected in nonpregnant patients. However, very low levels of latanoprost acid (51-59 pg/mL), the active metabolite, were detected with the maximal plasma concentration occurring 5 minutes after administration. When given intravenously to pregnant rabbits, the drug was shown to be abortifacient and teratogenic, but these effects were not observed in pregnant rats. Netarsudil (Rhopressa) (MW 454) is a kinase inhibitor indicated to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension. No quantifiable plasma concentrations of netarsudil were detected in 18 subjects. For the active metabolite, a plasma level of 0.11 ng/mL was found in one subject. Intravenous doses to pregnant rats and rabbits during organogenesis did not cause embryo-fetal adverse effects at clinically relevant systemic exposures.
Parathyroid hormone
Abaloparatide (Tymlos) (MW 3,961), given subcutaneously, is a human parathyroid hormone related peptide analog that is indicated for postmenopausal women with osteoporosis at high risk for fracture. Reproduction studies in animals have not been conducted. Because of the indication, it is doubtful if the agent will be used in pregnancy or during breastfeeding.
Respiratory
Benralizumab (Fasenra) (MW 150,000), given subcutaneously, is indicated for the add-on maintenance treatment of severe eosinophilic asthma. It is a human monoclonal IgG antibody and, though the MW is high, IgG antibodies are known to cross the placenta. Studies in monkeys found no evidence of fetal harm with intravenous doses throughout pregnancy that produced exposures up to about 310 times the exposure at the maximum recommended human dose.
The potential adverse effects in an infant when the mother is taking one of the above drugs while breastfeeding will be covered in my next column.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Oophorectomy for premenopausal breast cancer
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.
2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.
3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.
4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.
5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.
6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.
7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.
8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.
2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.
3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.
4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.
5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.
6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.
7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.
8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.
One-quarter of patients with breast cancer are diagnosed at a premenopausal age and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor–positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients.1
Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.
In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method.4 It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.
BRCA populations
For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with “triple-negative,” hormone receptor–negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis.5
Technique
When performing oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. In order to do this, it may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the “medial leaf” of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the “medial leaf” above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.
The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.
The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients.6 Patients who ask to “just take everything out while you are there” without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oophorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.
Consequences of ovarian ablation
It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses’ Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer.7,8
It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss this data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.
Hormone replacement therapy postoperatively
Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for “triple-negative” or hormone receptor–negative breast cancers as there is still some observed benefit of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.
Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor–positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.
Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.
2. Pagani O et al. N Engl J Med. 2014 Jul 10;371(12):107-18.
3. Francis PA et al. N Engl J Med. 2015 Jan 29;372(5):436-46.
4. Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(11):1093-102.
5. Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.
6. Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11):1434-40.
7. Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.
8. Rivera CM et al. Menopause. 2009 Jan-Feb;16:15-23.
How to harness value-based care codes
Many of you reading this column joined Medicare accountable care organizations (ACOs) sometime between 2011 and 2016. As the power of prevention, wellness, and the medical home model are starting to be realized and appreciated, those benefits may be swamped by two new Centers for Medicare and Medicaid Services value-based revenue streams that did not exist when many of you first joined your ACO.
The Medicare Access and CHIP Reauthorization Act (MACRA) was passed in 2015 and is just now being implemented. Value-based, fee-for-service payments started out rather modestly a few years ago as chronic care management codes, but they have exploded to include more than 20 codes, counting the new ones coming online in 2018. Let’s call them collectively value-based care codes, or VCCs.
Many practices are trying to understand and perform the basic requirements to avoid penalties under MACRA’s Merit-based Incentive Payment System (MIPS) program. Some primary care practices, however, see the upside potential and bonuses stacking up to 30% or more.
Did you know that even if you are in, let’s say, a basic Medicare Shared Savings Program ACO – the MSSP Track 1, with no exposure to risk – you get special treatment on reporting under MACRA as a MIPS Advanced Practice Model (APM)?
But more importantly, MACRA is a team game. Getting into an MSSP Track 1 is justified just to get practice for the care coordination you’ll need. Few physicians know that they are judged under MACRA MIPS for the total costs of their patients, not just their own costs. A primary care physician receives only up to 8% of the $10 million your patients consume on average. The best way to counter that is through an ACO.
Further, we are aware of ACOs that have chosen risk-taking Medicare models such as NextGen, even though they predict small losses. Those losses are because of the automatic 5% fee-for-service payment bump to its physicians for risk taking if they are in a MACRA Advanced Alternative Payment Model (AAPM).
There’s a wide range of primary care physicians who are seizing opportunities offered by VCCs.
A family physician friend of mine who practices in a rural area generated more than 50% of his revenue from value-based care coding last year. And he has personally generated more than $350,000 in additional annual revenue, not counting the revenue from additional medically necessary procedures revealed by this more proactive wellness assessment activity and early diagnoses.
On the other hand, because busy physicians have a hard time wading through all these regulations and implementing the required staff and technology changes, it is reported that only about 8% of physicians are employing even the chronic care management codes. And when they do, they only achieve an 18% eligible patient penetration. My friend has broken the code, so to speak; he has protocolized and templated the process, has happy patients, has an ongoing 93% penetration rate, and actually has more free time.
While you are busy saving lives, I have had the luxury of looking from a high level at these tectonic, value-based payment shifts. To me, it’s a no-brainer for a primary care physician to leverage their ACO to maximize all three revenue streams. Look at MACRA MIPS, MIPS-APM, and AAPM measures anew, and see how well they play into integrated care.
As quarterback of health care through the patient-centered medical home, you are in great position to drive substantial bonuses. Similarly, when one looks at VCCs, the ACO can: help you navigate through the paperwork, perform much of the required reporting, and select the highest value-adding initiatives to monitor and drive higher quality and shared savings for the ACO.
As readers know, we firmly believe that, to have sustained incentivization, every ACO needs to have a merit-based, shared savings distribution formula. Accordingly, your compensation should rise under MACRA, VCCs, and the ACO.
This shift to value care is hard. But your colleagues who have made these changes are enjoying practice as never before. Their professional and financial rewards have climbed. But, most important, their patients love it.
Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, a health care strategic consulting company. He has years of experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.
Many of you reading this column joined Medicare accountable care organizations (ACOs) sometime between 2011 and 2016. As the power of prevention, wellness, and the medical home model are starting to be realized and appreciated, those benefits may be swamped by two new Centers for Medicare and Medicaid Services value-based revenue streams that did not exist when many of you first joined your ACO.
The Medicare Access and CHIP Reauthorization Act (MACRA) was passed in 2015 and is just now being implemented. Value-based, fee-for-service payments started out rather modestly a few years ago as chronic care management codes, but they have exploded to include more than 20 codes, counting the new ones coming online in 2018. Let’s call them collectively value-based care codes, or VCCs.
Many practices are trying to understand and perform the basic requirements to avoid penalties under MACRA’s Merit-based Incentive Payment System (MIPS) program. Some primary care practices, however, see the upside potential and bonuses stacking up to 30% or more.
Did you know that even if you are in, let’s say, a basic Medicare Shared Savings Program ACO – the MSSP Track 1, with no exposure to risk – you get special treatment on reporting under MACRA as a MIPS Advanced Practice Model (APM)?
But more importantly, MACRA is a team game. Getting into an MSSP Track 1 is justified just to get practice for the care coordination you’ll need. Few physicians know that they are judged under MACRA MIPS for the total costs of their patients, not just their own costs. A primary care physician receives only up to 8% of the $10 million your patients consume on average. The best way to counter that is through an ACO.
Further, we are aware of ACOs that have chosen risk-taking Medicare models such as NextGen, even though they predict small losses. Those losses are because of the automatic 5% fee-for-service payment bump to its physicians for risk taking if they are in a MACRA Advanced Alternative Payment Model (AAPM).
There’s a wide range of primary care physicians who are seizing opportunities offered by VCCs.
A family physician friend of mine who practices in a rural area generated more than 50% of his revenue from value-based care coding last year. And he has personally generated more than $350,000 in additional annual revenue, not counting the revenue from additional medically necessary procedures revealed by this more proactive wellness assessment activity and early diagnoses.
On the other hand, because busy physicians have a hard time wading through all these regulations and implementing the required staff and technology changes, it is reported that only about 8% of physicians are employing even the chronic care management codes. And when they do, they only achieve an 18% eligible patient penetration. My friend has broken the code, so to speak; he has protocolized and templated the process, has happy patients, has an ongoing 93% penetration rate, and actually has more free time.
While you are busy saving lives, I have had the luxury of looking from a high level at these tectonic, value-based payment shifts. To me, it’s a no-brainer for a primary care physician to leverage their ACO to maximize all three revenue streams. Look at MACRA MIPS, MIPS-APM, and AAPM measures anew, and see how well they play into integrated care.
As quarterback of health care through the patient-centered medical home, you are in great position to drive substantial bonuses. Similarly, when one looks at VCCs, the ACO can: help you navigate through the paperwork, perform much of the required reporting, and select the highest value-adding initiatives to monitor and drive higher quality and shared savings for the ACO.
As readers know, we firmly believe that, to have sustained incentivization, every ACO needs to have a merit-based, shared savings distribution formula. Accordingly, your compensation should rise under MACRA, VCCs, and the ACO.
This shift to value care is hard. But your colleagues who have made these changes are enjoying practice as never before. Their professional and financial rewards have climbed. But, most important, their patients love it.
Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, a health care strategic consulting company. He has years of experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.
Many of you reading this column joined Medicare accountable care organizations (ACOs) sometime between 2011 and 2016. As the power of prevention, wellness, and the medical home model are starting to be realized and appreciated, those benefits may be swamped by two new Centers for Medicare and Medicaid Services value-based revenue streams that did not exist when many of you first joined your ACO.
The Medicare Access and CHIP Reauthorization Act (MACRA) was passed in 2015 and is just now being implemented. Value-based, fee-for-service payments started out rather modestly a few years ago as chronic care management codes, but they have exploded to include more than 20 codes, counting the new ones coming online in 2018. Let’s call them collectively value-based care codes, or VCCs.
Many practices are trying to understand and perform the basic requirements to avoid penalties under MACRA’s Merit-based Incentive Payment System (MIPS) program. Some primary care practices, however, see the upside potential and bonuses stacking up to 30% or more.
Did you know that even if you are in, let’s say, a basic Medicare Shared Savings Program ACO – the MSSP Track 1, with no exposure to risk – you get special treatment on reporting under MACRA as a MIPS Advanced Practice Model (APM)?
But more importantly, MACRA is a team game. Getting into an MSSP Track 1 is justified just to get practice for the care coordination you’ll need. Few physicians know that they are judged under MACRA MIPS for the total costs of their patients, not just their own costs. A primary care physician receives only up to 8% of the $10 million your patients consume on average. The best way to counter that is through an ACO.
Further, we are aware of ACOs that have chosen risk-taking Medicare models such as NextGen, even though they predict small losses. Those losses are because of the automatic 5% fee-for-service payment bump to its physicians for risk taking if they are in a MACRA Advanced Alternative Payment Model (AAPM).
There’s a wide range of primary care physicians who are seizing opportunities offered by VCCs.
A family physician friend of mine who practices in a rural area generated more than 50% of his revenue from value-based care coding last year. And he has personally generated more than $350,000 in additional annual revenue, not counting the revenue from additional medically necessary procedures revealed by this more proactive wellness assessment activity and early diagnoses.
On the other hand, because busy physicians have a hard time wading through all these regulations and implementing the required staff and technology changes, it is reported that only about 8% of physicians are employing even the chronic care management codes. And when they do, they only achieve an 18% eligible patient penetration. My friend has broken the code, so to speak; he has protocolized and templated the process, has happy patients, has an ongoing 93% penetration rate, and actually has more free time.
While you are busy saving lives, I have had the luxury of looking from a high level at these tectonic, value-based payment shifts. To me, it’s a no-brainer for a primary care physician to leverage their ACO to maximize all three revenue streams. Look at MACRA MIPS, MIPS-APM, and AAPM measures anew, and see how well they play into integrated care.
As quarterback of health care through the patient-centered medical home, you are in great position to drive substantial bonuses. Similarly, when one looks at VCCs, the ACO can: help you navigate through the paperwork, perform much of the required reporting, and select the highest value-adding initiatives to monitor and drive higher quality and shared savings for the ACO.
As readers know, we firmly believe that, to have sustained incentivization, every ACO needs to have a merit-based, shared savings distribution formula. Accordingly, your compensation should rise under MACRA, VCCs, and the ACO.
This shift to value care is hard. But your colleagues who have made these changes are enjoying practice as never before. Their professional and financial rewards have climbed. But, most important, their patients love it.
Mr. Bobbitt is head of the health law group at the Smith Anderson law firm in Raleigh, N.C. He is president of Value Health Partners, a health care strategic consulting company. He has years of experience assisting physicians form integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at [email protected] or 919-821-6612.
Universal depression screening for adolescents not without controversy
When 14-year-old Ryan saw his pediatrician for his annual physical this past August, he was asked a few quick questions about whether he was having any problems, if he was feeling depressed or anxious, and if there was anything he wanted to discuss. Ryan said no to each question, then the doctor examined him, reminded him to get a flu shot, and signed off on the forms he needed to play team sports in high school. The doctor assured Ryan’s mother that he was healthy, and the visit was over. Next August, Ryan’s exam will likely include a more detailed look at his mental health.
In February 2018, the American Academy of Pediatrics updated its guidelines on screening for depression in adolescents in primary care settings. The guidelines address the problem of undiagnosed and untreated psychiatric illness in children over the age of 10 years, the shortage of available mental health professionals, and techniques primary care physicians might use to address psychiatric needs in adolescents. The AAP guidelines include a new recommendation for universal screening with an assessment tool: “Adolescent patients ages 12 years and older should be screened annually for depression [MDD or depressive disorders] with a formal self-report screening tool either on paper or electronically.”
Dr. Liu noted that some of his patients drive 4-5 hours each way to see him in Omaha, then spend the night before making the return trip. “There is a dire shortage of pediatric mental health services in every state. This shifts the responsibility for care to pediatricians, teachers, and parents who often lack the resources to keep kids safe and well. It’s an unconscionable gap in care.”
Dr. Doran’s practice has not yet implemented the use of a written screening tool for all adolescents. He anticipates doing this soon because of the new guidelines, but he was not enthusiastic about the prospect. “ We are already loaded down with administrative tasks and screening requirements.” Of note, in Dr. Doran’s 35 years in clinical practice, no child under his care has died of suicide.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016).
When 14-year-old Ryan saw his pediatrician for his annual physical this past August, he was asked a few quick questions about whether he was having any problems, if he was feeling depressed or anxious, and if there was anything he wanted to discuss. Ryan said no to each question, then the doctor examined him, reminded him to get a flu shot, and signed off on the forms he needed to play team sports in high school. The doctor assured Ryan’s mother that he was healthy, and the visit was over. Next August, Ryan’s exam will likely include a more detailed look at his mental health.
In February 2018, the American Academy of Pediatrics updated its guidelines on screening for depression in adolescents in primary care settings. The guidelines address the problem of undiagnosed and untreated psychiatric illness in children over the age of 10 years, the shortage of available mental health professionals, and techniques primary care physicians might use to address psychiatric needs in adolescents. The AAP guidelines include a new recommendation for universal screening with an assessment tool: “Adolescent patients ages 12 years and older should be screened annually for depression [MDD or depressive disorders] with a formal self-report screening tool either on paper or electronically.”
Dr. Liu noted that some of his patients drive 4-5 hours each way to see him in Omaha, then spend the night before making the return trip. “There is a dire shortage of pediatric mental health services in every state. This shifts the responsibility for care to pediatricians, teachers, and parents who often lack the resources to keep kids safe and well. It’s an unconscionable gap in care.”
Dr. Doran’s practice has not yet implemented the use of a written screening tool for all adolescents. He anticipates doing this soon because of the new guidelines, but he was not enthusiastic about the prospect. “ We are already loaded down with administrative tasks and screening requirements.” Of note, in Dr. Doran’s 35 years in clinical practice, no child under his care has died of suicide.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016).
When 14-year-old Ryan saw his pediatrician for his annual physical this past August, he was asked a few quick questions about whether he was having any problems, if he was feeling depressed or anxious, and if there was anything he wanted to discuss. Ryan said no to each question, then the doctor examined him, reminded him to get a flu shot, and signed off on the forms he needed to play team sports in high school. The doctor assured Ryan’s mother that he was healthy, and the visit was over. Next August, Ryan’s exam will likely include a more detailed look at his mental health.
In February 2018, the American Academy of Pediatrics updated its guidelines on screening for depression in adolescents in primary care settings. The guidelines address the problem of undiagnosed and untreated psychiatric illness in children over the age of 10 years, the shortage of available mental health professionals, and techniques primary care physicians might use to address psychiatric needs in adolescents. The AAP guidelines include a new recommendation for universal screening with an assessment tool: “Adolescent patients ages 12 years and older should be screened annually for depression [MDD or depressive disorders] with a formal self-report screening tool either on paper or electronically.”
Dr. Liu noted that some of his patients drive 4-5 hours each way to see him in Omaha, then spend the night before making the return trip. “There is a dire shortage of pediatric mental health services in every state. This shifts the responsibility for care to pediatricians, teachers, and parents who often lack the resources to keep kids safe and well. It’s an unconscionable gap in care.”
Dr. Doran’s practice has not yet implemented the use of a written screening tool for all adolescents. He anticipates doing this soon because of the new guidelines, but he was not enthusiastic about the prospect. “ We are already loaded down with administrative tasks and screening requirements.” Of note, in Dr. Doran’s 35 years in clinical practice, no child under his care has died of suicide.
Dr. Miller is the coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016).
Experts explore issues, controversies around medical marijuana use
I live and work in Maryland, where medical marijuana dispensaries are just beginning to open. So far, my patients have been content to smoke illegal marijuana, even after my admonishments. Last week, however, a patient who suffers from chronic pain told me that one of her doctors suggested she try medical marijuana. What did I think? The patient is in her 70s, and she has not tolerated opiates. She lives an active life, and she drives. I didn’t know what to think and was left to tell her that I had no experience and would not object if she wanted to try it. The timing was right for “Issues and Controversies Around Marijuana Use: What’s the Buzz?” at the American Psychiatric Association’s annual meeting in New York this week.
William Iacono, PhD, a professor of psychiatry at the University of Minnesota, Minneapolis, started with a session called “Does Adolescent Marijuana Use Cause Cognitive Decline?” Dr. Iacono and all the speakers who followed him pointed out how difficult it is to research these issues. The research is largely retrospective, and the questions are complex. The degree of use is determined by self-report, and there are questions about acute versus chronic use, whether cognitive decline is temporary or permanent, whether the age of initiating drug use is important, and finally, which tests are used to measure cognitive abilities. Dr. Iacono noted that results are inconsistent and mentioned a large population study done in Dunedin, New Zealand, which measured a decrease in verbal IQ and vocabulary measures at age 38 years if the user began smoking cannabis as an adolescent. Dr. Iacono’s twin studies showed that marijuana users scored lower on these measures in childhood, well before they began smoking, and poor academic performance predisposes to marijuana use.
“Adolescents who use cannabis are not the same as those who don’t,” Dr. Iacono said, “and heavy or daily use does not cause cognitive decline in those who begin smoking as adults.”
Dr. Pearlson introduced the second speaker by saying, “It’s easier to get funding to show the ill effects of cannabis than to show medicinal effects.” Sue Sisley, MD, director of Midtown Roots, a medical marijuana dispensary in Phoenix, conducts cannabis trials for the treatment of PTSD in veterans and noted that she has had a long and difficult road with marijuana research, and hers is the only controlled trial on cannabis for PTSD. When her Schedule I license was approved by the Food and Drug Administration, she was able to receive marijuana from the National Institute on Drug Abuse that was grown by the University of Mississippi in Oxford – the only federal growing facility. The marijuana was delivered by FedEx, and the drug was the consistency of talcum powder. It was a challenge to find a lab that could verify the components of the test drug, and when she did, she found the tetrahydrocannabinol content was considerably lower than marijuana sold on the black market. Also, the product contained both mold and lead. “As a physician, how do you hand out mold weed to our veterans?”
Her trials are still in progress, and more veterans are needed. Anecdotally, she says, a decrease has been seen in the use of both opiates and Viagra by the research subjects.
Michael Stevens, PhD, adjunct professor of psychiatry at Yale University, New Haven, Conn., discussed the risk of motor vehicle accidents in marijuana smokers and the logistical issues enforcement poses for law enforcement officials. “There is evidence that marijuana increases the risk for accidents.” Dr. Stevens went on to say that the elevated risk is notably less than that associated with the use of alcohol or stimulants. Studying the effects of marijuana on driving is difficult, as driving simulators do not necessarily reflect on-road experiences, and cognitive testing does not always translate into impairment. “We can’t give marijuana to teens and test them, and you can’t tell people who smoke every day that you’ll check in with them in a few years and check their driving records.”
In terms of law enforcement issues, roadside sobriety tests have not been validated for marijuana use, and plasma levels of the drug drop within minutes of use. “The alcohol model works well with alcohol, but cannabis is not alcohol.”
Deborah Hasin, PhD, professor of epidemiology (psychiatry) at Columbia University, New York, talked about trends of cannabis use in the United States. “Looking at states before and after legalization, we see that there is an increase in both cannabis use and cannabis disorders in adults.” Adolescents, however, are not smoking more, and “Kids are just not socializing; they are in their bedrooms with their smartphones. Depression is increasing in teens, but substance abuse is not.”
The last speaker was Deepak Cyril D’Souza, MD, a professor of psychiatry at Yale University, who talked about cannabis and psychosis. He defined three distinct relationships: acute transient psychosis that resolves fairly quickly, acute persistent psychosis that takes days or weeks to resolve, and psychotic reactions that are associated with recurrent psychotic symptoms. Studies suggest that those who have a psychotic reaction to marijuana are at elevated risk of being diagnosed with schizophrenia later, and that timing of exposure to marijuana may be important.
With regard to the important question of whether marijuana causes schizophrenia, Dr. D’Souza noted that “it’s neither a necessary nor sufficient component, but it does appear it hastens psychosis in schizophrenia and earlier symptoms are associated with a worse prognosis.”
I’ll see what happens with my patient. A Canadian physician in the audience noted that he has treated thousands of patients, and most find medical marijuana to be helpful. In our country, marijuana continues to be a controversial topic with strong opinions about its usefulness and a conversation that is limited by our lack of research.
Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016). She practices in Baltimore.
I live and work in Maryland, where medical marijuana dispensaries are just beginning to open. So far, my patients have been content to smoke illegal marijuana, even after my admonishments. Last week, however, a patient who suffers from chronic pain told me that one of her doctors suggested she try medical marijuana. What did I think? The patient is in her 70s, and she has not tolerated opiates. She lives an active life, and she drives. I didn’t know what to think and was left to tell her that I had no experience and would not object if she wanted to try it. The timing was right for “Issues and Controversies Around Marijuana Use: What’s the Buzz?” at the American Psychiatric Association’s annual meeting in New York this week.
William Iacono, PhD, a professor of psychiatry at the University of Minnesota, Minneapolis, started with a session called “Does Adolescent Marijuana Use Cause Cognitive Decline?” Dr. Iacono and all the speakers who followed him pointed out how difficult it is to research these issues. The research is largely retrospective, and the questions are complex. The degree of use is determined by self-report, and there are questions about acute versus chronic use, whether cognitive decline is temporary or permanent, whether the age of initiating drug use is important, and finally, which tests are used to measure cognitive abilities. Dr. Iacono noted that results are inconsistent and mentioned a large population study done in Dunedin, New Zealand, which measured a decrease in verbal IQ and vocabulary measures at age 38 years if the user began smoking cannabis as an adolescent. Dr. Iacono’s twin studies showed that marijuana users scored lower on these measures in childhood, well before they began smoking, and poor academic performance predisposes to marijuana use.
“Adolescents who use cannabis are not the same as those who don’t,” Dr. Iacono said, “and heavy or daily use does not cause cognitive decline in those who begin smoking as adults.”
Dr. Pearlson introduced the second speaker by saying, “It’s easier to get funding to show the ill effects of cannabis than to show medicinal effects.” Sue Sisley, MD, director of Midtown Roots, a medical marijuana dispensary in Phoenix, conducts cannabis trials for the treatment of PTSD in veterans and noted that she has had a long and difficult road with marijuana research, and hers is the only controlled trial on cannabis for PTSD. When her Schedule I license was approved by the Food and Drug Administration, she was able to receive marijuana from the National Institute on Drug Abuse that was grown by the University of Mississippi in Oxford – the only federal growing facility. The marijuana was delivered by FedEx, and the drug was the consistency of talcum powder. It was a challenge to find a lab that could verify the components of the test drug, and when she did, she found the tetrahydrocannabinol content was considerably lower than marijuana sold on the black market. Also, the product contained both mold and lead. “As a physician, how do you hand out mold weed to our veterans?”
Her trials are still in progress, and more veterans are needed. Anecdotally, she says, a decrease has been seen in the use of both opiates and Viagra by the research subjects.
Michael Stevens, PhD, adjunct professor of psychiatry at Yale University, New Haven, Conn., discussed the risk of motor vehicle accidents in marijuana smokers and the logistical issues enforcement poses for law enforcement officials. “There is evidence that marijuana increases the risk for accidents.” Dr. Stevens went on to say that the elevated risk is notably less than that associated with the use of alcohol or stimulants. Studying the effects of marijuana on driving is difficult, as driving simulators do not necessarily reflect on-road experiences, and cognitive testing does not always translate into impairment. “We can’t give marijuana to teens and test them, and you can’t tell people who smoke every day that you’ll check in with them in a few years and check their driving records.”
In terms of law enforcement issues, roadside sobriety tests have not been validated for marijuana use, and plasma levels of the drug drop within minutes of use. “The alcohol model works well with alcohol, but cannabis is not alcohol.”
Deborah Hasin, PhD, professor of epidemiology (psychiatry) at Columbia University, New York, talked about trends of cannabis use in the United States. “Looking at states before and after legalization, we see that there is an increase in both cannabis use and cannabis disorders in adults.” Adolescents, however, are not smoking more, and “Kids are just not socializing; they are in their bedrooms with their smartphones. Depression is increasing in teens, but substance abuse is not.”
The last speaker was Deepak Cyril D’Souza, MD, a professor of psychiatry at Yale University, who talked about cannabis and psychosis. He defined three distinct relationships: acute transient psychosis that resolves fairly quickly, acute persistent psychosis that takes days or weeks to resolve, and psychotic reactions that are associated with recurrent psychotic symptoms. Studies suggest that those who have a psychotic reaction to marijuana are at elevated risk of being diagnosed with schizophrenia later, and that timing of exposure to marijuana may be important.
With regard to the important question of whether marijuana causes schizophrenia, Dr. D’Souza noted that “it’s neither a necessary nor sufficient component, but it does appear it hastens psychosis in schizophrenia and earlier symptoms are associated with a worse prognosis.”
I’ll see what happens with my patient. A Canadian physician in the audience noted that he has treated thousands of patients, and most find medical marijuana to be helpful. In our country, marijuana continues to be a controversial topic with strong opinions about its usefulness and a conversation that is limited by our lack of research.
Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016). She practices in Baltimore.
I live and work in Maryland, where medical marijuana dispensaries are just beginning to open. So far, my patients have been content to smoke illegal marijuana, even after my admonishments. Last week, however, a patient who suffers from chronic pain told me that one of her doctors suggested she try medical marijuana. What did I think? The patient is in her 70s, and she has not tolerated opiates. She lives an active life, and she drives. I didn’t know what to think and was left to tell her that I had no experience and would not object if she wanted to try it. The timing was right for “Issues and Controversies Around Marijuana Use: What’s the Buzz?” at the American Psychiatric Association’s annual meeting in New York this week.
William Iacono, PhD, a professor of psychiatry at the University of Minnesota, Minneapolis, started with a session called “Does Adolescent Marijuana Use Cause Cognitive Decline?” Dr. Iacono and all the speakers who followed him pointed out how difficult it is to research these issues. The research is largely retrospective, and the questions are complex. The degree of use is determined by self-report, and there are questions about acute versus chronic use, whether cognitive decline is temporary or permanent, whether the age of initiating drug use is important, and finally, which tests are used to measure cognitive abilities. Dr. Iacono noted that results are inconsistent and mentioned a large population study done in Dunedin, New Zealand, which measured a decrease in verbal IQ and vocabulary measures at age 38 years if the user began smoking cannabis as an adolescent. Dr. Iacono’s twin studies showed that marijuana users scored lower on these measures in childhood, well before they began smoking, and poor academic performance predisposes to marijuana use.
“Adolescents who use cannabis are not the same as those who don’t,” Dr. Iacono said, “and heavy or daily use does not cause cognitive decline in those who begin smoking as adults.”
Dr. Pearlson introduced the second speaker by saying, “It’s easier to get funding to show the ill effects of cannabis than to show medicinal effects.” Sue Sisley, MD, director of Midtown Roots, a medical marijuana dispensary in Phoenix, conducts cannabis trials for the treatment of PTSD in veterans and noted that she has had a long and difficult road with marijuana research, and hers is the only controlled trial on cannabis for PTSD. When her Schedule I license was approved by the Food and Drug Administration, she was able to receive marijuana from the National Institute on Drug Abuse that was grown by the University of Mississippi in Oxford – the only federal growing facility. The marijuana was delivered by FedEx, and the drug was the consistency of talcum powder. It was a challenge to find a lab that could verify the components of the test drug, and when she did, she found the tetrahydrocannabinol content was considerably lower than marijuana sold on the black market. Also, the product contained both mold and lead. “As a physician, how do you hand out mold weed to our veterans?”
Her trials are still in progress, and more veterans are needed. Anecdotally, she says, a decrease has been seen in the use of both opiates and Viagra by the research subjects.
Michael Stevens, PhD, adjunct professor of psychiatry at Yale University, New Haven, Conn., discussed the risk of motor vehicle accidents in marijuana smokers and the logistical issues enforcement poses for law enforcement officials. “There is evidence that marijuana increases the risk for accidents.” Dr. Stevens went on to say that the elevated risk is notably less than that associated with the use of alcohol or stimulants. Studying the effects of marijuana on driving is difficult, as driving simulators do not necessarily reflect on-road experiences, and cognitive testing does not always translate into impairment. “We can’t give marijuana to teens and test them, and you can’t tell people who smoke every day that you’ll check in with them in a few years and check their driving records.”
In terms of law enforcement issues, roadside sobriety tests have not been validated for marijuana use, and plasma levels of the drug drop within minutes of use. “The alcohol model works well with alcohol, but cannabis is not alcohol.”
Deborah Hasin, PhD, professor of epidemiology (psychiatry) at Columbia University, New York, talked about trends of cannabis use in the United States. “Looking at states before and after legalization, we see that there is an increase in both cannabis use and cannabis disorders in adults.” Adolescents, however, are not smoking more, and “Kids are just not socializing; they are in their bedrooms with their smartphones. Depression is increasing in teens, but substance abuse is not.”
The last speaker was Deepak Cyril D’Souza, MD, a professor of psychiatry at Yale University, who talked about cannabis and psychosis. He defined three distinct relationships: acute transient psychosis that resolves fairly quickly, acute persistent psychosis that takes days or weeks to resolve, and psychotic reactions that are associated with recurrent psychotic symptoms. Studies suggest that those who have a psychotic reaction to marijuana are at elevated risk of being diagnosed with schizophrenia later, and that timing of exposure to marijuana may be important.
With regard to the important question of whether marijuana causes schizophrenia, Dr. D’Souza noted that “it’s neither a necessary nor sufficient component, but it does appear it hastens psychosis in schizophrenia and earlier symptoms are associated with a worse prognosis.”
I’ll see what happens with my patient. A Canadian physician in the audience noted that he has treated thousands of patients, and most find medical marijuana to be helpful. In our country, marijuana continues to be a controversial topic with strong opinions about its usefulness and a conversation that is limited by our lack of research.
Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” (Baltimore: Johns Hopkins University Press, 2016). She practices in Baltimore.