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The Challenge of Delivering Mental Health Care in Rural Clinics
The nightmare of litigation: A survivor’s true story
The author reports no relevant financial relationships.
“I was stunned, bewildered, and disoriented. Surely this wasn’t happening to me. I felt cornered like a trapped animal and just had to escape so I spent most of the day wandering around in a daze. It was like living a dream—no, more like a nightmare.”
The victim of an accident, criminal assault, or terrorist attack? No, this was David, an obstetrician describing to me his reaction on being sued for medical malpractice. A day that started off as hectic but routine suddenly turned into a nightmare. Later, colleagues would tell him not to worry, that he’d be OK and that litigation was a “normal” part of medical practice. But it didn’t feel normal to him, as the memories of that day continued to replay in thoughts and dreams.
Malpractice liability may be omnipresent, but that doesn’t mean getting sued is a “normal” everyday hazard that Ob/Gyns should be able to take in stride. Litigation is frequently unfair, abusive, and traumatizing, and can cause acute stress disorder and even posttraumatic stress disorder (PTSD) in both physicians and patients.
David’s story
In this true story, an obstetrician suffering disabling litigation stress reclaims a sense of empowerment and control as he becomes aware of the nature of litigation stress. In the process, he learns how to listen, understand, and support patients, employees, and colleagues in times of stress.
During one-on-one telephone sessions, his trauma was acknowledged and named; his losses were identified and mourned in safety; and his isolation was relieved in a healing supportive relationship.
The initial shock
This was his first. “I was a litigation virgin,” he sardonically commented. “You know, when you’re jumping the waves in the ocean at high tide and then you become confident, you turn your back, and this big one hits you? It felt like that. I had just begun to relax, believing it wouldn’t happen to me. Then the lawsuit hit. It was a patient I’ve known for years. I delivered her other children and regarded her almost as a friend, someone I liked and trusted.
“I’ve made mistakes in the past but this wasn’t one of those times. It’s so unfair—instead of being grateful that I saved her 9.5-pound baby, she hunted down a lawyer on the Internet. The Web is full of them just waiting to pounce.”
The aftershocks
David recounted the journal articles1 he’d looked up, which recommended that he share his feelings with a trusted colleague. Other articles cautioned against a possible “discoverable” confidence.2 Colleagues’ attempts at reassurance did not really comfort him.
Sociable persons who have a thoughtful, active coping style and a strong sense of their ability to control their destiny have more capacity to resist stress.
Ask yourself:
- Am I a loner?
- Do I assign control of my destiny to others?
- Am I a perfectionist?
- Do I tend to beat up on myself when I miss the mark?
- Is my primary identity that of physician?
- Do I lack a community of support?
- Do I lack stress reduction practices?
- Do I suffer from burnout?
- Do I have a history of serious trauma?
If you answer yes to any of these questions, you are probably at greater risk of litigation stress. Begin attending to your personal needs and well-being now.
Expand your resilience. You have invested time and money in your education; now invest in yourself.
David contacted me when it became increasingly difficult for him to see patients. He said that he felt he had to be constantly on guard, watching every word and action as if patients were an enemy waiting to ambush him. He dreaded going to work and wondered if he should quit obstetrics.
No, he did not want to see a psychiatrist or a psychotherapist. He wasn’t crazy, he wasn’t thinking of suicide or anything like that, he said, and the last thing he needed was the credential committee of his local hospital breathing down his neck.
He spoke in a a lifeless monotone, reciting the facts of the case as he had told and retold them many times. He sighed often and used negative expressions such as can’t, but, should, have to, if only. He was articulating a lament—an expression of suffering and loss, which is not uncommon among physicians3,4 and patients.5 Within his narrative ran an unbroken thread of helplessness, grief, despair, and absence of meaning and hope.
Rather than premature reassurance and comfort, what David needed was to have his trauma named and acknowledged. Choosing my words carefully, I summarized his story and asked whether I had heard and understood him correctly. He verified that I had. Going a step further, I reflected back his underlying emotions as I had heard them—his feelings of fear, helplessness, sadness, isolation, betrayal, violation, anger, and injustice. Then I paused to create space for his response. Soon, the silence was interrupted by the sounds of his sobbing. When he regained his composure, David apologized for losing control. This lawsuit had been a huge strain, he explained.
Symptoms of acute stress reaction
I agreed, pointing out that he had probably experienced an acute stress reaction: feelings of intense fear, horror, and helplessness in response to an unusually traumatic event threatening death or serious physical injury to self or others.
This explained his fright and dazed disorientation on the day he learned of the litigation.6 While the lawsuit was not life-threatening, it threatened his identity, career, and survival as a physician.
Symptoms of PTSD
Usually acute stress reaction settles down, but sometimes it progresses beyond a month into posttraumatic stress disorder, a pervasive chronic anxiety disorder characterized by 3 clusters of symptoms:
- Recurrent, intrusive recollection of the events; recurrent flashbacks and dreams.
- Persistent avoidance of stimuli associated with the event; numbness, detachment, avoidance of patients.
- Persistent symptoms of increased arousal; insomnia, hypervigilance, irritability, difficulty with concentration.
“I am a rock” mentality may predispose to PTSD
Litigation, because of its protracted nature, is particularly retraumatizing. David concurred: “This explains why just opening a lawyer’s letter now causes my heart to pound.”
Unlike the military, physicians do not enter a stressful environment organized into teams. Should trauma and acute stress reaction occur, most physicians continue working despite their intense physical responses. There is little community support, so withdrawal and isolation is the norm, and this “norm” may predispose to posttraumatic stress disorder.
As a result, some physicians manifest behavioral problems such as being hyperreactive, aloof, or disruptive, or they abuse alcohol and drugs. Ironically, these behaviors probably lay groundwork for additional lawsuits.7
Counting up the losses
David asked what I meant by “losses.” I explained that the nature of trauma is to create loss.
- Together we listed his loss of:
trust
safety
peace of mind
sense of justice
integrity of personal boundaries
control
self-esteem
self-confidence
passion
idealism
If you notice that you are stunned, bewildered, and feeling overwhelmed, even disoriented, accept that you may not be able to think clearly for a while. Avoid complex tasks and major decisions.
Take care of your physical health. Obstetricians take sleep deprivation, lack of exercise, long hours, and irregular eating habits for granted. This, however, is not the time to neglect your basic needs. If necessary, take time off (though many prefer to keep to a regular, albeit moderated, familiar schedule).
Do not isolate yourself. Share your feelings with those you can trust. Consider seeing an individual, such as a psychotherapist, who is trained to listen therapeutically. Do not use your lawyer for this purpose.
Limit use of substances (such as sedatives, hypnotics, alcohol) and limit activities (burying yourself in work or exercise) aimed at numbing your emotions.
Conserve your energy. You have limited control over legal proceedings. You can, however, apply your energy to improving your well-being.
If you develop symptoms of depression, do not hesitate to seek psychiatric help and certainly do not attempt to self-medicate.
For many reasons, not the least being shame, physicians avoid consulting a mental health professional and repercussions can be serious.16
Remember your life partner, children, and others around you may be affected too. Be gentle with them.
The power to choose how to respond
While he could not stop the lawsuit, he did have the power to choose how to respond to it. It was his choice whether to be demolished by this lawsuit or to use it to grow personally and professionally. If he agreed, I would partner him in transforming his suffering into growth. On the other hand, should his symptoms not recede, he would need to see a psychiatrist.
By now I had:
- validated his trauma, losses, and suffering
- provided him a cognitive framework
- interrupted his lament
- created safety for him to express his emotions
- emphasized he was not helpless, and that he had choices
- offered to partner with him, thereby relieving his isolation
- role-modeled listening
- offered him hope and a sense of some control.
A set-up for litigation stress
Surveys reveal that many medical students are exposed to serious trauma such as sexual abuse or domestic violence prior to entering medical school.8 They then enter medical training, which has been described as a “neglectful abusive family system,”9 and which adds trauma and toxic shame—this continues into a career punctuated with acute episodes of severe trauma such as medical errors, unexpected death of patients, and litigation stress.
Breast cancer, traumatic birth cause acute stress
David read books on trauma10 and suffering,11,12 and began to explore ways to apply his new insight. He read journal articles that described acute stress reaction in patients diagnosed with breast cancer,13 traumatic birth,14 and spontaneous abortion.15 Now he understood why patients sometimes left his office bewildered and disoriented, unable to retain any information, and why patients with chronic trauma experience functional somatic symptoms. He also learned how to respond more effectively.
The outcome: Self-empowerment
Together we studied his written narratives of patient encounters and did role plays of these encounters. He was a good student, and his ability to communicate empathy and support eventually matched his technical proficiency. Increasingly, not only patients, but also employees and colleagues turned to him for listening in times of stress. Their positive feedback enhanced his sense of well-being. His newly acquired empowerment and sense of control was key to his success.
Over the course of 8 months, he traveled full circle from trauma victim to healer.
Litigation stress: Take it seriously
When taken seriously, much can be done to transform litigation stress into physician empowerment. Studies need to be done on stress disorders in physicians, so as to refute the culture of denial that exists around the trauma inflicted by malpractice litigation. Innovative programs need to be developed to minimize the harmful effect of litigation and to support physicians suffering litigation stress.
1. Meier D, Back A, Morrison R. The inner life of physicians and care of the seriously ill. JAMA. 2001;286:3007-3014.
2. Physician Insurance Litigation Stress Support Services. http://www.phyins.com/pi/claims/stress.html
3. Daugird A, Spencer D. Physician reactions to the health care revolution: a grief model approach. Arch Fam Med. 1996;5:497-500.
4. Loder D. The saddest day of my life. Berks County Medical Record. 1998(5);89:6.-
5. Bub B. The Lament, Hidden Key to Effective Listening. Medical Humanities. In press.
6. Christensen JF, Levinson W, Dunn PM. The impact of perceived mistakes on physicians. J Gen Intern Med. 1992;7:424-431.
7. Kennedy J. Physicians’ feelings about themselves and their patients. Letter. JAMA. 2002;287:1113.-
8. Ambuel B, Butler D, Hamberger LK, et al. Female and male students’ exposure to violence: impact on well-being and perceived capacity to help battered women. J Comparative Fam Studies. 2003;34:113-135.
9. McKegney C. Medical Education: A neglectful and abusive family system. Fam Med. 1989;452-457.
10. Herman JL. Trauma and Recovery. London: Rivers Oram Press; 1997.
11. Schneider JM. Finding My Way. Healing and Transformation through Loss and Grief. Seasons Press. 1994.
12. Frankl VE. Man’s Search for Meaning. Beacon Press. 1946.
13. McGarvey EL, Canterbury RJ, Cohen RB. Evidence of acute stress disorder after diagnosis of cancer. Southern Med J. 1998;91:864-866.
14. Reynolds JL. Posttraumatic stress disorder after childbirth: the phenomenon of traumatic birth. Can Med Assoc J. 1997;156:831-835.
15. Bowles SV, James LC, Solursh DS, Yancey MK, Epperly TD, Folen RA, Masone M. Acute and posttraumatic stress disorder after spontaneous abortion. Am Fam Phys. 2000;61:1689-1696.
16. Brunk D. Suicide is top cause of early death in physicians–far higher than in general population. http://www.findarticles.com/p/articles/mi_m0CYD/is_5_38/ai_98830125
The author reports no relevant financial relationships.
“I was stunned, bewildered, and disoriented. Surely this wasn’t happening to me. I felt cornered like a trapped animal and just had to escape so I spent most of the day wandering around in a daze. It was like living a dream—no, more like a nightmare.”
The victim of an accident, criminal assault, or terrorist attack? No, this was David, an obstetrician describing to me his reaction on being sued for medical malpractice. A day that started off as hectic but routine suddenly turned into a nightmare. Later, colleagues would tell him not to worry, that he’d be OK and that litigation was a “normal” part of medical practice. But it didn’t feel normal to him, as the memories of that day continued to replay in thoughts and dreams.
Malpractice liability may be omnipresent, but that doesn’t mean getting sued is a “normal” everyday hazard that Ob/Gyns should be able to take in stride. Litigation is frequently unfair, abusive, and traumatizing, and can cause acute stress disorder and even posttraumatic stress disorder (PTSD) in both physicians and patients.
David’s story
In this true story, an obstetrician suffering disabling litigation stress reclaims a sense of empowerment and control as he becomes aware of the nature of litigation stress. In the process, he learns how to listen, understand, and support patients, employees, and colleagues in times of stress.
During one-on-one telephone sessions, his trauma was acknowledged and named; his losses were identified and mourned in safety; and his isolation was relieved in a healing supportive relationship.
The initial shock
This was his first. “I was a litigation virgin,” he sardonically commented. “You know, when you’re jumping the waves in the ocean at high tide and then you become confident, you turn your back, and this big one hits you? It felt like that. I had just begun to relax, believing it wouldn’t happen to me. Then the lawsuit hit. It was a patient I’ve known for years. I delivered her other children and regarded her almost as a friend, someone I liked and trusted.
“I’ve made mistakes in the past but this wasn’t one of those times. It’s so unfair—instead of being grateful that I saved her 9.5-pound baby, she hunted down a lawyer on the Internet. The Web is full of them just waiting to pounce.”
The aftershocks
David recounted the journal articles1 he’d looked up, which recommended that he share his feelings with a trusted colleague. Other articles cautioned against a possible “discoverable” confidence.2 Colleagues’ attempts at reassurance did not really comfort him.
Sociable persons who have a thoughtful, active coping style and a strong sense of their ability to control their destiny have more capacity to resist stress.
Ask yourself:
- Am I a loner?
- Do I assign control of my destiny to others?
- Am I a perfectionist?
- Do I tend to beat up on myself when I miss the mark?
- Is my primary identity that of physician?
- Do I lack a community of support?
- Do I lack stress reduction practices?
- Do I suffer from burnout?
- Do I have a history of serious trauma?
If you answer yes to any of these questions, you are probably at greater risk of litigation stress. Begin attending to your personal needs and well-being now.
Expand your resilience. You have invested time and money in your education; now invest in yourself.
David contacted me when it became increasingly difficult for him to see patients. He said that he felt he had to be constantly on guard, watching every word and action as if patients were an enemy waiting to ambush him. He dreaded going to work and wondered if he should quit obstetrics.
No, he did not want to see a psychiatrist or a psychotherapist. He wasn’t crazy, he wasn’t thinking of suicide or anything like that, he said, and the last thing he needed was the credential committee of his local hospital breathing down his neck.
He spoke in a a lifeless monotone, reciting the facts of the case as he had told and retold them many times. He sighed often and used negative expressions such as can’t, but, should, have to, if only. He was articulating a lament—an expression of suffering and loss, which is not uncommon among physicians3,4 and patients.5 Within his narrative ran an unbroken thread of helplessness, grief, despair, and absence of meaning and hope.
Rather than premature reassurance and comfort, what David needed was to have his trauma named and acknowledged. Choosing my words carefully, I summarized his story and asked whether I had heard and understood him correctly. He verified that I had. Going a step further, I reflected back his underlying emotions as I had heard them—his feelings of fear, helplessness, sadness, isolation, betrayal, violation, anger, and injustice. Then I paused to create space for his response. Soon, the silence was interrupted by the sounds of his sobbing. When he regained his composure, David apologized for losing control. This lawsuit had been a huge strain, he explained.
Symptoms of acute stress reaction
I agreed, pointing out that he had probably experienced an acute stress reaction: feelings of intense fear, horror, and helplessness in response to an unusually traumatic event threatening death or serious physical injury to self or others.
This explained his fright and dazed disorientation on the day he learned of the litigation.6 While the lawsuit was not life-threatening, it threatened his identity, career, and survival as a physician.
Symptoms of PTSD
Usually acute stress reaction settles down, but sometimes it progresses beyond a month into posttraumatic stress disorder, a pervasive chronic anxiety disorder characterized by 3 clusters of symptoms:
- Recurrent, intrusive recollection of the events; recurrent flashbacks and dreams.
- Persistent avoidance of stimuli associated with the event; numbness, detachment, avoidance of patients.
- Persistent symptoms of increased arousal; insomnia, hypervigilance, irritability, difficulty with concentration.
“I am a rock” mentality may predispose to PTSD
Litigation, because of its protracted nature, is particularly retraumatizing. David concurred: “This explains why just opening a lawyer’s letter now causes my heart to pound.”
Unlike the military, physicians do not enter a stressful environment organized into teams. Should trauma and acute stress reaction occur, most physicians continue working despite their intense physical responses. There is little community support, so withdrawal and isolation is the norm, and this “norm” may predispose to posttraumatic stress disorder.
As a result, some physicians manifest behavioral problems such as being hyperreactive, aloof, or disruptive, or they abuse alcohol and drugs. Ironically, these behaviors probably lay groundwork for additional lawsuits.7
Counting up the losses
David asked what I meant by “losses.” I explained that the nature of trauma is to create loss.
- Together we listed his loss of:
trust
safety
peace of mind
sense of justice
integrity of personal boundaries
control
self-esteem
self-confidence
passion
idealism
If you notice that you are stunned, bewildered, and feeling overwhelmed, even disoriented, accept that you may not be able to think clearly for a while. Avoid complex tasks and major decisions.
Take care of your physical health. Obstetricians take sleep deprivation, lack of exercise, long hours, and irregular eating habits for granted. This, however, is not the time to neglect your basic needs. If necessary, take time off (though many prefer to keep to a regular, albeit moderated, familiar schedule).
Do not isolate yourself. Share your feelings with those you can trust. Consider seeing an individual, such as a psychotherapist, who is trained to listen therapeutically. Do not use your lawyer for this purpose.
Limit use of substances (such as sedatives, hypnotics, alcohol) and limit activities (burying yourself in work or exercise) aimed at numbing your emotions.
Conserve your energy. You have limited control over legal proceedings. You can, however, apply your energy to improving your well-being.
If you develop symptoms of depression, do not hesitate to seek psychiatric help and certainly do not attempt to self-medicate.
For many reasons, not the least being shame, physicians avoid consulting a mental health professional and repercussions can be serious.16
Remember your life partner, children, and others around you may be affected too. Be gentle with them.
The power to choose how to respond
While he could not stop the lawsuit, he did have the power to choose how to respond to it. It was his choice whether to be demolished by this lawsuit or to use it to grow personally and professionally. If he agreed, I would partner him in transforming his suffering into growth. On the other hand, should his symptoms not recede, he would need to see a psychiatrist.
By now I had:
- validated his trauma, losses, and suffering
- provided him a cognitive framework
- interrupted his lament
- created safety for him to express his emotions
- emphasized he was not helpless, and that he had choices
- offered to partner with him, thereby relieving his isolation
- role-modeled listening
- offered him hope and a sense of some control.
A set-up for litigation stress
Surveys reveal that many medical students are exposed to serious trauma such as sexual abuse or domestic violence prior to entering medical school.8 They then enter medical training, which has been described as a “neglectful abusive family system,”9 and which adds trauma and toxic shame—this continues into a career punctuated with acute episodes of severe trauma such as medical errors, unexpected death of patients, and litigation stress.
Breast cancer, traumatic birth cause acute stress
David read books on trauma10 and suffering,11,12 and began to explore ways to apply his new insight. He read journal articles that described acute stress reaction in patients diagnosed with breast cancer,13 traumatic birth,14 and spontaneous abortion.15 Now he understood why patients sometimes left his office bewildered and disoriented, unable to retain any information, and why patients with chronic trauma experience functional somatic symptoms. He also learned how to respond more effectively.
The outcome: Self-empowerment
Together we studied his written narratives of patient encounters and did role plays of these encounters. He was a good student, and his ability to communicate empathy and support eventually matched his technical proficiency. Increasingly, not only patients, but also employees and colleagues turned to him for listening in times of stress. Their positive feedback enhanced his sense of well-being. His newly acquired empowerment and sense of control was key to his success.
Over the course of 8 months, he traveled full circle from trauma victim to healer.
Litigation stress: Take it seriously
When taken seriously, much can be done to transform litigation stress into physician empowerment. Studies need to be done on stress disorders in physicians, so as to refute the culture of denial that exists around the trauma inflicted by malpractice litigation. Innovative programs need to be developed to minimize the harmful effect of litigation and to support physicians suffering litigation stress.
The author reports no relevant financial relationships.
“I was stunned, bewildered, and disoriented. Surely this wasn’t happening to me. I felt cornered like a trapped animal and just had to escape so I spent most of the day wandering around in a daze. It was like living a dream—no, more like a nightmare.”
The victim of an accident, criminal assault, or terrorist attack? No, this was David, an obstetrician describing to me his reaction on being sued for medical malpractice. A day that started off as hectic but routine suddenly turned into a nightmare. Later, colleagues would tell him not to worry, that he’d be OK and that litigation was a “normal” part of medical practice. But it didn’t feel normal to him, as the memories of that day continued to replay in thoughts and dreams.
Malpractice liability may be omnipresent, but that doesn’t mean getting sued is a “normal” everyday hazard that Ob/Gyns should be able to take in stride. Litigation is frequently unfair, abusive, and traumatizing, and can cause acute stress disorder and even posttraumatic stress disorder (PTSD) in both physicians and patients.
David’s story
In this true story, an obstetrician suffering disabling litigation stress reclaims a sense of empowerment and control as he becomes aware of the nature of litigation stress. In the process, he learns how to listen, understand, and support patients, employees, and colleagues in times of stress.
During one-on-one telephone sessions, his trauma was acknowledged and named; his losses were identified and mourned in safety; and his isolation was relieved in a healing supportive relationship.
The initial shock
This was his first. “I was a litigation virgin,” he sardonically commented. “You know, when you’re jumping the waves in the ocean at high tide and then you become confident, you turn your back, and this big one hits you? It felt like that. I had just begun to relax, believing it wouldn’t happen to me. Then the lawsuit hit. It was a patient I’ve known for years. I delivered her other children and regarded her almost as a friend, someone I liked and trusted.
“I’ve made mistakes in the past but this wasn’t one of those times. It’s so unfair—instead of being grateful that I saved her 9.5-pound baby, she hunted down a lawyer on the Internet. The Web is full of them just waiting to pounce.”
The aftershocks
David recounted the journal articles1 he’d looked up, which recommended that he share his feelings with a trusted colleague. Other articles cautioned against a possible “discoverable” confidence.2 Colleagues’ attempts at reassurance did not really comfort him.
Sociable persons who have a thoughtful, active coping style and a strong sense of their ability to control their destiny have more capacity to resist stress.
Ask yourself:
- Am I a loner?
- Do I assign control of my destiny to others?
- Am I a perfectionist?
- Do I tend to beat up on myself when I miss the mark?
- Is my primary identity that of physician?
- Do I lack a community of support?
- Do I lack stress reduction practices?
- Do I suffer from burnout?
- Do I have a history of serious trauma?
If you answer yes to any of these questions, you are probably at greater risk of litigation stress. Begin attending to your personal needs and well-being now.
Expand your resilience. You have invested time and money in your education; now invest in yourself.
David contacted me when it became increasingly difficult for him to see patients. He said that he felt he had to be constantly on guard, watching every word and action as if patients were an enemy waiting to ambush him. He dreaded going to work and wondered if he should quit obstetrics.
No, he did not want to see a psychiatrist or a psychotherapist. He wasn’t crazy, he wasn’t thinking of suicide or anything like that, he said, and the last thing he needed was the credential committee of his local hospital breathing down his neck.
He spoke in a a lifeless monotone, reciting the facts of the case as he had told and retold them many times. He sighed often and used negative expressions such as can’t, but, should, have to, if only. He was articulating a lament—an expression of suffering and loss, which is not uncommon among physicians3,4 and patients.5 Within his narrative ran an unbroken thread of helplessness, grief, despair, and absence of meaning and hope.
Rather than premature reassurance and comfort, what David needed was to have his trauma named and acknowledged. Choosing my words carefully, I summarized his story and asked whether I had heard and understood him correctly. He verified that I had. Going a step further, I reflected back his underlying emotions as I had heard them—his feelings of fear, helplessness, sadness, isolation, betrayal, violation, anger, and injustice. Then I paused to create space for his response. Soon, the silence was interrupted by the sounds of his sobbing. When he regained his composure, David apologized for losing control. This lawsuit had been a huge strain, he explained.
Symptoms of acute stress reaction
I agreed, pointing out that he had probably experienced an acute stress reaction: feelings of intense fear, horror, and helplessness in response to an unusually traumatic event threatening death or serious physical injury to self or others.
This explained his fright and dazed disorientation on the day he learned of the litigation.6 While the lawsuit was not life-threatening, it threatened his identity, career, and survival as a physician.
Symptoms of PTSD
Usually acute stress reaction settles down, but sometimes it progresses beyond a month into posttraumatic stress disorder, a pervasive chronic anxiety disorder characterized by 3 clusters of symptoms:
- Recurrent, intrusive recollection of the events; recurrent flashbacks and dreams.
- Persistent avoidance of stimuli associated with the event; numbness, detachment, avoidance of patients.
- Persistent symptoms of increased arousal; insomnia, hypervigilance, irritability, difficulty with concentration.
“I am a rock” mentality may predispose to PTSD
Litigation, because of its protracted nature, is particularly retraumatizing. David concurred: “This explains why just opening a lawyer’s letter now causes my heart to pound.”
Unlike the military, physicians do not enter a stressful environment organized into teams. Should trauma and acute stress reaction occur, most physicians continue working despite their intense physical responses. There is little community support, so withdrawal and isolation is the norm, and this “norm” may predispose to posttraumatic stress disorder.
As a result, some physicians manifest behavioral problems such as being hyperreactive, aloof, or disruptive, or they abuse alcohol and drugs. Ironically, these behaviors probably lay groundwork for additional lawsuits.7
Counting up the losses
David asked what I meant by “losses.” I explained that the nature of trauma is to create loss.
- Together we listed his loss of:
trust
safety
peace of mind
sense of justice
integrity of personal boundaries
control
self-esteem
self-confidence
passion
idealism
If you notice that you are stunned, bewildered, and feeling overwhelmed, even disoriented, accept that you may not be able to think clearly for a while. Avoid complex tasks and major decisions.
Take care of your physical health. Obstetricians take sleep deprivation, lack of exercise, long hours, and irregular eating habits for granted. This, however, is not the time to neglect your basic needs. If necessary, take time off (though many prefer to keep to a regular, albeit moderated, familiar schedule).
Do not isolate yourself. Share your feelings with those you can trust. Consider seeing an individual, such as a psychotherapist, who is trained to listen therapeutically. Do not use your lawyer for this purpose.
Limit use of substances (such as sedatives, hypnotics, alcohol) and limit activities (burying yourself in work or exercise) aimed at numbing your emotions.
Conserve your energy. You have limited control over legal proceedings. You can, however, apply your energy to improving your well-being.
If you develop symptoms of depression, do not hesitate to seek psychiatric help and certainly do not attempt to self-medicate.
For many reasons, not the least being shame, physicians avoid consulting a mental health professional and repercussions can be serious.16
Remember your life partner, children, and others around you may be affected too. Be gentle with them.
The power to choose how to respond
While he could not stop the lawsuit, he did have the power to choose how to respond to it. It was his choice whether to be demolished by this lawsuit or to use it to grow personally and professionally. If he agreed, I would partner him in transforming his suffering into growth. On the other hand, should his symptoms not recede, he would need to see a psychiatrist.
By now I had:
- validated his trauma, losses, and suffering
- provided him a cognitive framework
- interrupted his lament
- created safety for him to express his emotions
- emphasized he was not helpless, and that he had choices
- offered to partner with him, thereby relieving his isolation
- role-modeled listening
- offered him hope and a sense of some control.
A set-up for litigation stress
Surveys reveal that many medical students are exposed to serious trauma such as sexual abuse or domestic violence prior to entering medical school.8 They then enter medical training, which has been described as a “neglectful abusive family system,”9 and which adds trauma and toxic shame—this continues into a career punctuated with acute episodes of severe trauma such as medical errors, unexpected death of patients, and litigation stress.
Breast cancer, traumatic birth cause acute stress
David read books on trauma10 and suffering,11,12 and began to explore ways to apply his new insight. He read journal articles that described acute stress reaction in patients diagnosed with breast cancer,13 traumatic birth,14 and spontaneous abortion.15 Now he understood why patients sometimes left his office bewildered and disoriented, unable to retain any information, and why patients with chronic trauma experience functional somatic symptoms. He also learned how to respond more effectively.
The outcome: Self-empowerment
Together we studied his written narratives of patient encounters and did role plays of these encounters. He was a good student, and his ability to communicate empathy and support eventually matched his technical proficiency. Increasingly, not only patients, but also employees and colleagues turned to him for listening in times of stress. Their positive feedback enhanced his sense of well-being. His newly acquired empowerment and sense of control was key to his success.
Over the course of 8 months, he traveled full circle from trauma victim to healer.
Litigation stress: Take it seriously
When taken seriously, much can be done to transform litigation stress into physician empowerment. Studies need to be done on stress disorders in physicians, so as to refute the culture of denial that exists around the trauma inflicted by malpractice litigation. Innovative programs need to be developed to minimize the harmful effect of litigation and to support physicians suffering litigation stress.
1. Meier D, Back A, Morrison R. The inner life of physicians and care of the seriously ill. JAMA. 2001;286:3007-3014.
2. Physician Insurance Litigation Stress Support Services. http://www.phyins.com/pi/claims/stress.html
3. Daugird A, Spencer D. Physician reactions to the health care revolution: a grief model approach. Arch Fam Med. 1996;5:497-500.
4. Loder D. The saddest day of my life. Berks County Medical Record. 1998(5);89:6.-
5. Bub B. The Lament, Hidden Key to Effective Listening. Medical Humanities. In press.
6. Christensen JF, Levinson W, Dunn PM. The impact of perceived mistakes on physicians. J Gen Intern Med. 1992;7:424-431.
7. Kennedy J. Physicians’ feelings about themselves and their patients. Letter. JAMA. 2002;287:1113.-
8. Ambuel B, Butler D, Hamberger LK, et al. Female and male students’ exposure to violence: impact on well-being and perceived capacity to help battered women. J Comparative Fam Studies. 2003;34:113-135.
9. McKegney C. Medical Education: A neglectful and abusive family system. Fam Med. 1989;452-457.
10. Herman JL. Trauma and Recovery. London: Rivers Oram Press; 1997.
11. Schneider JM. Finding My Way. Healing and Transformation through Loss and Grief. Seasons Press. 1994.
12. Frankl VE. Man’s Search for Meaning. Beacon Press. 1946.
13. McGarvey EL, Canterbury RJ, Cohen RB. Evidence of acute stress disorder after diagnosis of cancer. Southern Med J. 1998;91:864-866.
14. Reynolds JL. Posttraumatic stress disorder after childbirth: the phenomenon of traumatic birth. Can Med Assoc J. 1997;156:831-835.
15. Bowles SV, James LC, Solursh DS, Yancey MK, Epperly TD, Folen RA, Masone M. Acute and posttraumatic stress disorder after spontaneous abortion. Am Fam Phys. 2000;61:1689-1696.
16. Brunk D. Suicide is top cause of early death in physicians–far higher than in general population. http://www.findarticles.com/p/articles/mi_m0CYD/is_5_38/ai_98830125
1. Meier D, Back A, Morrison R. The inner life of physicians and care of the seriously ill. JAMA. 2001;286:3007-3014.
2. Physician Insurance Litigation Stress Support Services. http://www.phyins.com/pi/claims/stress.html
3. Daugird A, Spencer D. Physician reactions to the health care revolution: a grief model approach. Arch Fam Med. 1996;5:497-500.
4. Loder D. The saddest day of my life. Berks County Medical Record. 1998(5);89:6.-
5. Bub B. The Lament, Hidden Key to Effective Listening. Medical Humanities. In press.
6. Christensen JF, Levinson W, Dunn PM. The impact of perceived mistakes on physicians. J Gen Intern Med. 1992;7:424-431.
7. Kennedy J. Physicians’ feelings about themselves and their patients. Letter. JAMA. 2002;287:1113.-
8. Ambuel B, Butler D, Hamberger LK, et al. Female and male students’ exposure to violence: impact on well-being and perceived capacity to help battered women. J Comparative Fam Studies. 2003;34:113-135.
9. McKegney C. Medical Education: A neglectful and abusive family system. Fam Med. 1989;452-457.
10. Herman JL. Trauma and Recovery. London: Rivers Oram Press; 1997.
11. Schneider JM. Finding My Way. Healing and Transformation through Loss and Grief. Seasons Press. 1994.
12. Frankl VE. Man’s Search for Meaning. Beacon Press. 1946.
13. McGarvey EL, Canterbury RJ, Cohen RB. Evidence of acute stress disorder after diagnosis of cancer. Southern Med J. 1998;91:864-866.
14. Reynolds JL. Posttraumatic stress disorder after childbirth: the phenomenon of traumatic birth. Can Med Assoc J. 1997;156:831-835.
15. Bowles SV, James LC, Solursh DS, Yancey MK, Epperly TD, Folen RA, Masone M. Acute and posttraumatic stress disorder after spontaneous abortion. Am Fam Phys. 2000;61:1689-1696.
16. Brunk D. Suicide is top cause of early death in physicians–far higher than in general population. http://www.findarticles.com/p/articles/mi_m0CYD/is_5_38/ai_98830125
New screening basics for the generalist
Overall, you must determine the extent to which you will provide and interpret genetic testing and when to refer patients to a specialist. This article aims to simplify that decision by reviewing guidelines and key studies in 3 areas:
- For genetic carrier screening for people of Ashkenazi Jewish heritage, add familial dysautonomia to the list of screened diseases.
- Screening for Down syndrome is now possible in the first trimester.
- Greater genetic risks may be present among children born as a result of assisted reproductive technology (ART), although it’s unclear whether the cause is their parents’ infertility or ART itself.
On the plus side, molecular DNA diagnostics are increasingly sophisticated, readily available, and cost-efficient. The downside: As the list of recommended studies grows, successful testing programs are harder to achieve because of the need to educate patients—and yourself—about each test.
Preconception testing may be especially advisable in women with infertility because it can identify carriers and detect conditions related to infertility or its treatment. With 1% of US births attributable to ART, the possibility of genetic effects continues to raise concern.
Add another disease to genetic carrier screening
ACOG Committee Opinion #298: Prenatal and preconception carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2004;104:425–428.
Add familial dysautonomia to carrier screening when patients—or their partners—are of Ashkenazi Jewish heritage. That’s the advice from an American College of Obstetricians and Gynecologists (ACOG) committee opinion. Also conduct previously recommended screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, and advise patients that testing is available for several other diseases as well (TABLE 1). For Tay-Sachs disease, screening also is urged for patients of French Canadian and Cajun descent.
ACOG emphasizes the importance of assessing these risks prior to pregnancy to allow time for the partner to be tested, if necessary.
Among the Ashkenazi Jewish population, DNA testing detects more than 95% of carriers of autosomal disorders by analyzing the small number of mutations responsible. Tay-Sachs was the first disease for which mutations were identified.
Familial dysautonomia is caused by a single mutation in the gene IKBKAP in more than 99% of affected patients. It has a carrier rate (1/32) similar to that of Tay-Sachs disease (1/30) and involves substantial morbidity of the autonomic and sensory nervous system, with symptoms such as abnormal sweating, pain/temperature insensitivity, and labile blood pressure. Treatment may relieve symptoms, but does not cure the disease.
Refer non-Ashkenazi partners of identified carriers. Although non-Ashkenazi partners are less likely to be carriers, the exact carrier frequency and detection rates for these people are unknown (except for Tay-Sachs disease and cystic fibrosis). In these situations, it may be wise to refer the patient and her partner for genetic counseling to clarify the sensitivity of DNA analysis and the advisability of possible alternative testing by enzyme analysis.
What a generalist should offer. Because the availability of genetic testing will continue to increase, ACOG recommends that generalists provide:
- patient education on the disorders,
- referral sources for additional counseling and prenatal diagnostic testing,
- informed consent when obtaining samples for genetic testing, and
- assurance of confidentiality.
Screen for Down syndrome in the first trimester
Screening for Down syndrome is now available in the first trimester; ACOG recommends using ultrasound and maternal serum screening, with 3 criteria:
- standardized, continuous quality assurance,
- ability to counsel patients about the testing options, and
- access to appropriate diagnostic testing.
TABLE 2).
Integrated versus contingency screening. “Integrated” screening combines information from the first trimester (nuchal lucency and serum screen) with serum screening in the second trimester. This approach yields the lowest screen-positive rate (2.6%) and a high detection rate (90%), but has an important shortcoming: The results are not disclosed until the second trimester.
“Contingency” screening is emerging as an alternative: High first-trimester risks are relayed to the patient, while women with low screen values are excused from further testing. Patients with intermediate risk proceed to second-trimester serum screening.
Disadvantages of this approach include the need to coordinate the various steps and adequately inform the patient of them.
Added value of first-trimester nuchal lucency screening. Increased nuchal translucency alone is an important screen for structural abnormalities and adverse pregnancy outcomes. If a karyotypically normal fetus has an increased first-trimester nuchal lucency, the possibility of a structural anomaly on second-trimester ultrasound increases 2-to 10-fold. Absolute risk rises with increasing nuchal lucency.
Since an average of 10% to 15% of the identified anomalies are cardiac defects, fetal echocardiogram and a comprehensive fetal survey are appropriate in the second trimester.
TABLE 2
Detecting Down syndrome: Which test is best?
| MODALITY | SCREEN-POSITIVE RATE | DETECTION RATE |
|---|---|---|
| Maternal age >35 years | 18% | 30% |
| Triple screen (MSAFP, beta-hCG, estriol) | 5% | 65% |
| Quad screen (triple plus inhibin) | 5% | 75% |
| First-trimester (nuchal lucency, PAPP-A, free beta-hCG) | 5% | 80% |
| Integrated (first-trimester nuchal lucency and serum screen combined with second-trimester serum screen) | 2.5% | 90% |
| MSAFP = maternal serum alpha-fetoprotein, PAPP-A = pregnancy-associated plasma protein-A | ||
REFERENCE
1. Wapner R, Thom E, Simpsoon JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003;349:1405-1413.
Are children conceived with ART at increased risk?
Children born as a result of ART may face a higher risk of inherited disorders and congenital malformations, but it is unclear whether the risks are due to their parents’ infertility or to ART.
For this reason, it may be wise to refer ART patients for additional genetic counseling and fetal structural surveillance by ultrasound.
Schieve and colleagues attempted to clarify the risks by reviewing the theoretical and empiric literature. Two studies provide the bulk of evidence. In Western Australia, the background risk of birth defects doubled in infants conceived with ART: 9% risk in both intracytoplasmic sperm injection and IVF patients, compared with 4% with spontaneous conception.1 This study is notable because ART programs are more highly regulated in Australia and similar methods were used to ascertain congenital anomalies in both groups.
A comparable study2 in Sweden also noted an increased risk, but attributed it to the underlying cause of the parents’ infertility rather than to ART itself. The reason: The increased risk disappeared when the authors adjusted for the period of “involuntary childlessness.” However, they provided very little detail on how involuntary childlessness was defined and “whether and how strongly this measure is correlated with infertility severity in Sweden.”2
Imprinting disorders among ART offspring. Schieve et al also explored imprinting disorders, since diseases such as Beckwith-Wiedemann syndrome are attributed to them. Imprinting is an epigenetic phenomenon in which the allele of only 1 parent is active at a particular gene locus. The inactive—or imprinted—allele is rendered nonfunctional, often through methylation. Gametogenesis and preimplantation are times of increased imprinting. Identified imprinted genes include those that control embryonic growth and differentiation.
Analyses of Beckwith-Wiedemann syndrome registries in the United States, France, and the UK3-5 revealed a 3- to 6-fold increase in ART conception among infants with the syndrome. Case reports of other rare imprinted disorders such as Angelman syndrome and retinoblastoma are also beginning to appear.
Direct treatment effect not established. According to Schieve et al and others, evidence of an increased risk of defects following ART does not indicate whether a direct treatment effect is present. Future studies that address methodological flaws are sure to be time-consuming; they also will require large sample sizes and consistent ascertainment and ART treatment.
Dr. Wilkins-Haug reports no relevant financial relationships.
1. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725-730.
2. Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-based study. Hum Reprod. 2001;16:504-509.
3. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156-160.
4. Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART) [published erratum appears in J Med Genet. 2003;40:304]. J Med Genet. 2003;40:62-64.
5. Gicquel C, Gaston V, Mandelbaum J, et al. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338-1341.
Overall, you must determine the extent to which you will provide and interpret genetic testing and when to refer patients to a specialist. This article aims to simplify that decision by reviewing guidelines and key studies in 3 areas:
- For genetic carrier screening for people of Ashkenazi Jewish heritage, add familial dysautonomia to the list of screened diseases.
- Screening for Down syndrome is now possible in the first trimester.
- Greater genetic risks may be present among children born as a result of assisted reproductive technology (ART), although it’s unclear whether the cause is their parents’ infertility or ART itself.
On the plus side, molecular DNA diagnostics are increasingly sophisticated, readily available, and cost-efficient. The downside: As the list of recommended studies grows, successful testing programs are harder to achieve because of the need to educate patients—and yourself—about each test.
Preconception testing may be especially advisable in women with infertility because it can identify carriers and detect conditions related to infertility or its treatment. With 1% of US births attributable to ART, the possibility of genetic effects continues to raise concern.
Add another disease to genetic carrier screening
ACOG Committee Opinion #298: Prenatal and preconception carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2004;104:425–428.
Add familial dysautonomia to carrier screening when patients—or their partners—are of Ashkenazi Jewish heritage. That’s the advice from an American College of Obstetricians and Gynecologists (ACOG) committee opinion. Also conduct previously recommended screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, and advise patients that testing is available for several other diseases as well (TABLE 1). For Tay-Sachs disease, screening also is urged for patients of French Canadian and Cajun descent.
ACOG emphasizes the importance of assessing these risks prior to pregnancy to allow time for the partner to be tested, if necessary.
Among the Ashkenazi Jewish population, DNA testing detects more than 95% of carriers of autosomal disorders by analyzing the small number of mutations responsible. Tay-Sachs was the first disease for which mutations were identified.
Familial dysautonomia is caused by a single mutation in the gene IKBKAP in more than 99% of affected patients. It has a carrier rate (1/32) similar to that of Tay-Sachs disease (1/30) and involves substantial morbidity of the autonomic and sensory nervous system, with symptoms such as abnormal sweating, pain/temperature insensitivity, and labile blood pressure. Treatment may relieve symptoms, but does not cure the disease.
Refer non-Ashkenazi partners of identified carriers. Although non-Ashkenazi partners are less likely to be carriers, the exact carrier frequency and detection rates for these people are unknown (except for Tay-Sachs disease and cystic fibrosis). In these situations, it may be wise to refer the patient and her partner for genetic counseling to clarify the sensitivity of DNA analysis and the advisability of possible alternative testing by enzyme analysis.
What a generalist should offer. Because the availability of genetic testing will continue to increase, ACOG recommends that generalists provide:
- patient education on the disorders,
- referral sources for additional counseling and prenatal diagnostic testing,
- informed consent when obtaining samples for genetic testing, and
- assurance of confidentiality.
Screen for Down syndrome in the first trimester
Screening for Down syndrome is now available in the first trimester; ACOG recommends using ultrasound and maternal serum screening, with 3 criteria:
- standardized, continuous quality assurance,
- ability to counsel patients about the testing options, and
- access to appropriate diagnostic testing.
TABLE 2).
Integrated versus contingency screening. “Integrated” screening combines information from the first trimester (nuchal lucency and serum screen) with serum screening in the second trimester. This approach yields the lowest screen-positive rate (2.6%) and a high detection rate (90%), but has an important shortcoming: The results are not disclosed until the second trimester.
“Contingency” screening is emerging as an alternative: High first-trimester risks are relayed to the patient, while women with low screen values are excused from further testing. Patients with intermediate risk proceed to second-trimester serum screening.
Disadvantages of this approach include the need to coordinate the various steps and adequately inform the patient of them.
Added value of first-trimester nuchal lucency screening. Increased nuchal translucency alone is an important screen for structural abnormalities and adverse pregnancy outcomes. If a karyotypically normal fetus has an increased first-trimester nuchal lucency, the possibility of a structural anomaly on second-trimester ultrasound increases 2-to 10-fold. Absolute risk rises with increasing nuchal lucency.
Since an average of 10% to 15% of the identified anomalies are cardiac defects, fetal echocardiogram and a comprehensive fetal survey are appropriate in the second trimester.
TABLE 2
Detecting Down syndrome: Which test is best?
| MODALITY | SCREEN-POSITIVE RATE | DETECTION RATE |
|---|---|---|
| Maternal age >35 years | 18% | 30% |
| Triple screen (MSAFP, beta-hCG, estriol) | 5% | 65% |
| Quad screen (triple plus inhibin) | 5% | 75% |
| First-trimester (nuchal lucency, PAPP-A, free beta-hCG) | 5% | 80% |
| Integrated (first-trimester nuchal lucency and serum screen combined with second-trimester serum screen) | 2.5% | 90% |
| MSAFP = maternal serum alpha-fetoprotein, PAPP-A = pregnancy-associated plasma protein-A | ||
REFERENCE
1. Wapner R, Thom E, Simpsoon JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003;349:1405-1413.
Are children conceived with ART at increased risk?
Children born as a result of ART may face a higher risk of inherited disorders and congenital malformations, but it is unclear whether the risks are due to their parents’ infertility or to ART.
For this reason, it may be wise to refer ART patients for additional genetic counseling and fetal structural surveillance by ultrasound.
Schieve and colleagues attempted to clarify the risks by reviewing the theoretical and empiric literature. Two studies provide the bulk of evidence. In Western Australia, the background risk of birth defects doubled in infants conceived with ART: 9% risk in both intracytoplasmic sperm injection and IVF patients, compared with 4% with spontaneous conception.1 This study is notable because ART programs are more highly regulated in Australia and similar methods were used to ascertain congenital anomalies in both groups.
A comparable study2 in Sweden also noted an increased risk, but attributed it to the underlying cause of the parents’ infertility rather than to ART itself. The reason: The increased risk disappeared when the authors adjusted for the period of “involuntary childlessness.” However, they provided very little detail on how involuntary childlessness was defined and “whether and how strongly this measure is correlated with infertility severity in Sweden.”2
Imprinting disorders among ART offspring. Schieve et al also explored imprinting disorders, since diseases such as Beckwith-Wiedemann syndrome are attributed to them. Imprinting is an epigenetic phenomenon in which the allele of only 1 parent is active at a particular gene locus. The inactive—or imprinted—allele is rendered nonfunctional, often through methylation. Gametogenesis and preimplantation are times of increased imprinting. Identified imprinted genes include those that control embryonic growth and differentiation.
Analyses of Beckwith-Wiedemann syndrome registries in the United States, France, and the UK3-5 revealed a 3- to 6-fold increase in ART conception among infants with the syndrome. Case reports of other rare imprinted disorders such as Angelman syndrome and retinoblastoma are also beginning to appear.
Direct treatment effect not established. According to Schieve et al and others, evidence of an increased risk of defects following ART does not indicate whether a direct treatment effect is present. Future studies that address methodological flaws are sure to be time-consuming; they also will require large sample sizes and consistent ascertainment and ART treatment.
Dr. Wilkins-Haug reports no relevant financial relationships.
Overall, you must determine the extent to which you will provide and interpret genetic testing and when to refer patients to a specialist. This article aims to simplify that decision by reviewing guidelines and key studies in 3 areas:
- For genetic carrier screening for people of Ashkenazi Jewish heritage, add familial dysautonomia to the list of screened diseases.
- Screening for Down syndrome is now possible in the first trimester.
- Greater genetic risks may be present among children born as a result of assisted reproductive technology (ART), although it’s unclear whether the cause is their parents’ infertility or ART itself.
On the plus side, molecular DNA diagnostics are increasingly sophisticated, readily available, and cost-efficient. The downside: As the list of recommended studies grows, successful testing programs are harder to achieve because of the need to educate patients—and yourself—about each test.
Preconception testing may be especially advisable in women with infertility because it can identify carriers and detect conditions related to infertility or its treatment. With 1% of US births attributable to ART, the possibility of genetic effects continues to raise concern.
Add another disease to genetic carrier screening
ACOG Committee Opinion #298: Prenatal and preconception carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2004;104:425–428.
Add familial dysautonomia to carrier screening when patients—or their partners—are of Ashkenazi Jewish heritage. That’s the advice from an American College of Obstetricians and Gynecologists (ACOG) committee opinion. Also conduct previously recommended screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, and advise patients that testing is available for several other diseases as well (TABLE 1). For Tay-Sachs disease, screening also is urged for patients of French Canadian and Cajun descent.
ACOG emphasizes the importance of assessing these risks prior to pregnancy to allow time for the partner to be tested, if necessary.
Among the Ashkenazi Jewish population, DNA testing detects more than 95% of carriers of autosomal disorders by analyzing the small number of mutations responsible. Tay-Sachs was the first disease for which mutations were identified.
Familial dysautonomia is caused by a single mutation in the gene IKBKAP in more than 99% of affected patients. It has a carrier rate (1/32) similar to that of Tay-Sachs disease (1/30) and involves substantial morbidity of the autonomic and sensory nervous system, with symptoms such as abnormal sweating, pain/temperature insensitivity, and labile blood pressure. Treatment may relieve symptoms, but does not cure the disease.
Refer non-Ashkenazi partners of identified carriers. Although non-Ashkenazi partners are less likely to be carriers, the exact carrier frequency and detection rates for these people are unknown (except for Tay-Sachs disease and cystic fibrosis). In these situations, it may be wise to refer the patient and her partner for genetic counseling to clarify the sensitivity of DNA analysis and the advisability of possible alternative testing by enzyme analysis.
What a generalist should offer. Because the availability of genetic testing will continue to increase, ACOG recommends that generalists provide:
- patient education on the disorders,
- referral sources for additional counseling and prenatal diagnostic testing,
- informed consent when obtaining samples for genetic testing, and
- assurance of confidentiality.
Screen for Down syndrome in the first trimester
Screening for Down syndrome is now available in the first trimester; ACOG recommends using ultrasound and maternal serum screening, with 3 criteria:
- standardized, continuous quality assurance,
- ability to counsel patients about the testing options, and
- access to appropriate diagnostic testing.
TABLE 2).
Integrated versus contingency screening. “Integrated” screening combines information from the first trimester (nuchal lucency and serum screen) with serum screening in the second trimester. This approach yields the lowest screen-positive rate (2.6%) and a high detection rate (90%), but has an important shortcoming: The results are not disclosed until the second trimester.
“Contingency” screening is emerging as an alternative: High first-trimester risks are relayed to the patient, while women with low screen values are excused from further testing. Patients with intermediate risk proceed to second-trimester serum screening.
Disadvantages of this approach include the need to coordinate the various steps and adequately inform the patient of them.
Added value of first-trimester nuchal lucency screening. Increased nuchal translucency alone is an important screen for structural abnormalities and adverse pregnancy outcomes. If a karyotypically normal fetus has an increased first-trimester nuchal lucency, the possibility of a structural anomaly on second-trimester ultrasound increases 2-to 10-fold. Absolute risk rises with increasing nuchal lucency.
Since an average of 10% to 15% of the identified anomalies are cardiac defects, fetal echocardiogram and a comprehensive fetal survey are appropriate in the second trimester.
TABLE 2
Detecting Down syndrome: Which test is best?
| MODALITY | SCREEN-POSITIVE RATE | DETECTION RATE |
|---|---|---|
| Maternal age >35 years | 18% | 30% |
| Triple screen (MSAFP, beta-hCG, estriol) | 5% | 65% |
| Quad screen (triple plus inhibin) | 5% | 75% |
| First-trimester (nuchal lucency, PAPP-A, free beta-hCG) | 5% | 80% |
| Integrated (first-trimester nuchal lucency and serum screen combined with second-trimester serum screen) | 2.5% | 90% |
| MSAFP = maternal serum alpha-fetoprotein, PAPP-A = pregnancy-associated plasma protein-A | ||
REFERENCE
1. Wapner R, Thom E, Simpsoon JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003;349:1405-1413.
Are children conceived with ART at increased risk?
Children born as a result of ART may face a higher risk of inherited disorders and congenital malformations, but it is unclear whether the risks are due to their parents’ infertility or to ART.
For this reason, it may be wise to refer ART patients for additional genetic counseling and fetal structural surveillance by ultrasound.
Schieve and colleagues attempted to clarify the risks by reviewing the theoretical and empiric literature. Two studies provide the bulk of evidence. In Western Australia, the background risk of birth defects doubled in infants conceived with ART: 9% risk in both intracytoplasmic sperm injection and IVF patients, compared with 4% with spontaneous conception.1 This study is notable because ART programs are more highly regulated in Australia and similar methods were used to ascertain congenital anomalies in both groups.
A comparable study2 in Sweden also noted an increased risk, but attributed it to the underlying cause of the parents’ infertility rather than to ART itself. The reason: The increased risk disappeared when the authors adjusted for the period of “involuntary childlessness.” However, they provided very little detail on how involuntary childlessness was defined and “whether and how strongly this measure is correlated with infertility severity in Sweden.”2
Imprinting disorders among ART offspring. Schieve et al also explored imprinting disorders, since diseases such as Beckwith-Wiedemann syndrome are attributed to them. Imprinting is an epigenetic phenomenon in which the allele of only 1 parent is active at a particular gene locus. The inactive—or imprinted—allele is rendered nonfunctional, often through methylation. Gametogenesis and preimplantation are times of increased imprinting. Identified imprinted genes include those that control embryonic growth and differentiation.
Analyses of Beckwith-Wiedemann syndrome registries in the United States, France, and the UK3-5 revealed a 3- to 6-fold increase in ART conception among infants with the syndrome. Case reports of other rare imprinted disorders such as Angelman syndrome and retinoblastoma are also beginning to appear.
Direct treatment effect not established. According to Schieve et al and others, evidence of an increased risk of defects following ART does not indicate whether a direct treatment effect is present. Future studies that address methodological flaws are sure to be time-consuming; they also will require large sample sizes and consistent ascertainment and ART treatment.
Dr. Wilkins-Haug reports no relevant financial relationships.
1. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725-730.
2. Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-based study. Hum Reprod. 2001;16:504-509.
3. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156-160.
4. Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART) [published erratum appears in J Med Genet. 2003;40:304]. J Med Genet. 2003;40:62-64.
5. Gicquel C, Gaston V, Mandelbaum J, et al. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338-1341.
1. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725-730.
2. Ericson A, Kallen B. Congenital malformations in infants born after IVF: a population-based study. Hum Reprod. 2001;16:504-509.
3. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156-160.
4. Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART) [published erratum appears in J Med Genet. 2003;40:304]. J Med Genet. 2003;40:62-64.
5. Gicquel C, Gaston V, Mandelbaum J, et al. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338-1341.
How to judge an herbal remedy
Safety issues surrounding herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. In addition, the preparations are often poor in quality. One reason: They are inadequately regulated, a problem many experts hope to change. Cost evaluations of herbal medicines are not available.
This article offers guidelines for prescribing herbal medications, as well as advice on when they are unwise.
TABLE 1
10 best-selling herbal medicines
| RANK | HERB | RETAIL SALES ($ MILLIONS)* |
|---|---|---|
| 1 | Ginkgo biloba | $46 |
| 2 | Echinacea | $40 |
| 3 | Garlic | $35 |
| 4 | Ginseng | $31 |
| 5 | Soy | $28 |
| 6 | Saw palmetto | $25 |
| 7 | St John’s wort | $24 |
| 8 | Valerian | $12 |
| 9 | Cranberry | $10 |
| 10 | Black cohosh | $10 |
| * US, 2001 data | ||
Is the herb effective for the patient’s condition?
Although data are incomplete, some treatments have shown promise (TABLE 2), and findings indicate serious adverse effects of certain treatments (TABLE 3).
Besides safety, the critical question is: Does the remedy work for the patient’s condition? Do not prescribe or recommend an herbal remedy if the answer is not a firm yes.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases, it is unclear which constituents produce the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component.
To optimize the reproducibility of efficacy studies, extracts must be sufficiently characterized. This is often achieved by standardizing the amount of a single key constituent (eg, a pharmacologically active ingredient or a marker suitable substance if such an ingredient is unknown).
Once the dilemma of standardization is solved, herbal medicines are scrutinized in much the same way as other drugs. The literature contains several randomized, clinical trials and systematic reviews/meta-analyses of these studies.3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books recently were published.3-6
Unfortunately, systematic reviews are often limited by the paucity and varied methodological quality of the primary studies,3,7 and research funds are generally scarce, in part because plants cannot be patented.
Generalizations about the efficacy of herbal medicines are not possible. Each remedy must be judged on its own merits. Some herbal products have demon strated efficacy for certain conditions, while others have not. Overall, few products have been subjected to extensive clinical testing.3
The bottom line? As a review in the New England Journal of Medicine concluded, “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy.”7
Tradition is no guarantee, as in the case of kava
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can cause both desirable and undesirable effects. TABLE 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries, apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic agent,9 but it was recently associated with several cases of serious liver damage.10 As a result, it was withdrawn from the markets of several European countries, and the US Food and Drug Administration (FDA) has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines can interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence would be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) are contaminated with heavy metals13; contain misidentified, toxic herbal ingredients14; or are adulterated with prescription drugs.15 Be sure an herbal medication cannot cause harm before prescribing or recommending it.
TABLE 3
7 herbal medicines associated with serious adverse effects*
| COMMON (LATIN) NAME | INDICATION | ADVERSE EFFECTS (EXAMPLES) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribed drugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| * This is a sampling only. Also, without positive safety data, herbal medications cannot be considered safe for pregnant or nursing women. | ||
Uneven quality marks herbal medicines
The quality of an herbal preparation contributes to its efficacy and safety. Herbal dietary supplements usually are unregulated as drugs and can vary widely in quality—to the point of being ineffective.7,16
In the United States, herbal preparations must meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus, they are marketed without FDA approval of their efficacy and safety. The DSHEA prohibits companies from making medical claims for dietary supplements, but does allow structure or functional claims. If safety concerns arise, the burden of proof lies not with the manufacturer, but with the FDA.
Many experts believe this regulation is insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon require efficacy to be based on bibliographic data, and safety will be governed as it is with conventional drugs.17
Not enough data to base decisions on cost
As a general rule, clinicians should try to recommend treatments that save money for patients and the health-care system. Although herbal medications are relatively inexpensive, few proper economic analyses exist.18,19 So far, only 1 cost evaluation20 of an herbal medicine has been published. This study involved treatment of symptomatic chronic venous insufficiency and compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds; the treatments were comparable.
For the prescribing physician, this means decisions cannot be based on conclusive cost-analyses. Until such studies are available, decisions must be informed by our knowledge of the efficacy, safety, and quality of herbal medications.
One of 5 Ayurvedic herbal medicine products may contain potentially toxic levels of lead, mercury, and/or arsenic, according to a study in the December 15 issue of JAMA. The Ayurvedic tradition is a holistic healing system that originated in India. When researchers tested Ayurvedic products produced in South Asia and sold in the Boston area, 14 of 70 contained heavy metals. If taken according to the package directions, the preparations would exceed published standards for the metals, some of them by a huge margin.
Pharmaceuticals in an herbal remedy?
Among other hazards detected in herbal products are undeclared prescription drugs mixed into the ingredients of some Chinese preparations, according to the FDA. And last May, Consumer Reports identified 12 dietary supplements “too dangerous to be on the market,” yet all were readily available in stores or online. They include comfrey, androstenedione, chaparral, and kava.
Pose the question
All the more reason to ask patients what products they may be using. Ask specifically about herbal or natural remedies, since many people do not consider them drugs and fail to disclose them to physicians.
—The editors
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA. 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram. 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med. 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol. 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed. 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci. 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg. 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther. 2001;70:497-504.
14. Nortier JL, Martinez MC. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med. 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA. 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia. 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Kernick DE, ed. Getting Health Economics into Practice. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeconomics. 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag. 1997;2:86-91.
Safety issues surrounding herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. In addition, the preparations are often poor in quality. One reason: They are inadequately regulated, a problem many experts hope to change. Cost evaluations of herbal medicines are not available.
This article offers guidelines for prescribing herbal medications, as well as advice on when they are unwise.
TABLE 1
10 best-selling herbal medicines
| RANK | HERB | RETAIL SALES ($ MILLIONS)* |
|---|---|---|
| 1 | Ginkgo biloba | $46 |
| 2 | Echinacea | $40 |
| 3 | Garlic | $35 |
| 4 | Ginseng | $31 |
| 5 | Soy | $28 |
| 6 | Saw palmetto | $25 |
| 7 | St John’s wort | $24 |
| 8 | Valerian | $12 |
| 9 | Cranberry | $10 |
| 10 | Black cohosh | $10 |
| * US, 2001 data | ||
Is the herb effective for the patient’s condition?
Although data are incomplete, some treatments have shown promise (TABLE 2), and findings indicate serious adverse effects of certain treatments (TABLE 3).
Besides safety, the critical question is: Does the remedy work for the patient’s condition? Do not prescribe or recommend an herbal remedy if the answer is not a firm yes.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases, it is unclear which constituents produce the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component.
To optimize the reproducibility of efficacy studies, extracts must be sufficiently characterized. This is often achieved by standardizing the amount of a single key constituent (eg, a pharmacologically active ingredient or a marker suitable substance if such an ingredient is unknown).
Once the dilemma of standardization is solved, herbal medicines are scrutinized in much the same way as other drugs. The literature contains several randomized, clinical trials and systematic reviews/meta-analyses of these studies.3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books recently were published.3-6
Unfortunately, systematic reviews are often limited by the paucity and varied methodological quality of the primary studies,3,7 and research funds are generally scarce, in part because plants cannot be patented.
Generalizations about the efficacy of herbal medicines are not possible. Each remedy must be judged on its own merits. Some herbal products have demon strated efficacy for certain conditions, while others have not. Overall, few products have been subjected to extensive clinical testing.3
The bottom line? As a review in the New England Journal of Medicine concluded, “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy.”7
Tradition is no guarantee, as in the case of kava
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can cause both desirable and undesirable effects. TABLE 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries, apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic agent,9 but it was recently associated with several cases of serious liver damage.10 As a result, it was withdrawn from the markets of several European countries, and the US Food and Drug Administration (FDA) has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines can interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence would be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) are contaminated with heavy metals13; contain misidentified, toxic herbal ingredients14; or are adulterated with prescription drugs.15 Be sure an herbal medication cannot cause harm before prescribing or recommending it.
TABLE 3
7 herbal medicines associated with serious adverse effects*
| COMMON (LATIN) NAME | INDICATION | ADVERSE EFFECTS (EXAMPLES) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribed drugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| * This is a sampling only. Also, without positive safety data, herbal medications cannot be considered safe for pregnant or nursing women. | ||
Uneven quality marks herbal medicines
The quality of an herbal preparation contributes to its efficacy and safety. Herbal dietary supplements usually are unregulated as drugs and can vary widely in quality—to the point of being ineffective.7,16
In the United States, herbal preparations must meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus, they are marketed without FDA approval of their efficacy and safety. The DSHEA prohibits companies from making medical claims for dietary supplements, but does allow structure or functional claims. If safety concerns arise, the burden of proof lies not with the manufacturer, but with the FDA.
Many experts believe this regulation is insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon require efficacy to be based on bibliographic data, and safety will be governed as it is with conventional drugs.17
Not enough data to base decisions on cost
As a general rule, clinicians should try to recommend treatments that save money for patients and the health-care system. Although herbal medications are relatively inexpensive, few proper economic analyses exist.18,19 So far, only 1 cost evaluation20 of an herbal medicine has been published. This study involved treatment of symptomatic chronic venous insufficiency and compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds; the treatments were comparable.
For the prescribing physician, this means decisions cannot be based on conclusive cost-analyses. Until such studies are available, decisions must be informed by our knowledge of the efficacy, safety, and quality of herbal medications.
One of 5 Ayurvedic herbal medicine products may contain potentially toxic levels of lead, mercury, and/or arsenic, according to a study in the December 15 issue of JAMA. The Ayurvedic tradition is a holistic healing system that originated in India. When researchers tested Ayurvedic products produced in South Asia and sold in the Boston area, 14 of 70 contained heavy metals. If taken according to the package directions, the preparations would exceed published standards for the metals, some of them by a huge margin.
Pharmaceuticals in an herbal remedy?
Among other hazards detected in herbal products are undeclared prescription drugs mixed into the ingredients of some Chinese preparations, according to the FDA. And last May, Consumer Reports identified 12 dietary supplements “too dangerous to be on the market,” yet all were readily available in stores or online. They include comfrey, androstenedione, chaparral, and kava.
Pose the question
All the more reason to ask patients what products they may be using. Ask specifically about herbal or natural remedies, since many people do not consider them drugs and fail to disclose them to physicians.
—The editors
Safety issues surrounding herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. In addition, the preparations are often poor in quality. One reason: They are inadequately regulated, a problem many experts hope to change. Cost evaluations of herbal medicines are not available.
This article offers guidelines for prescribing herbal medications, as well as advice on when they are unwise.
TABLE 1
10 best-selling herbal medicines
| RANK | HERB | RETAIL SALES ($ MILLIONS)* |
|---|---|---|
| 1 | Ginkgo biloba | $46 |
| 2 | Echinacea | $40 |
| 3 | Garlic | $35 |
| 4 | Ginseng | $31 |
| 5 | Soy | $28 |
| 6 | Saw palmetto | $25 |
| 7 | St John’s wort | $24 |
| 8 | Valerian | $12 |
| 9 | Cranberry | $10 |
| 10 | Black cohosh | $10 |
| * US, 2001 data | ||
Is the herb effective for the patient’s condition?
Although data are incomplete, some treatments have shown promise (TABLE 2), and findings indicate serious adverse effects of certain treatments (TABLE 3).
Besides safety, the critical question is: Does the remedy work for the patient’s condition? Do not prescribe or recommend an herbal remedy if the answer is not a firm yes.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases, it is unclear which constituents produce the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component.
To optimize the reproducibility of efficacy studies, extracts must be sufficiently characterized. This is often achieved by standardizing the amount of a single key constituent (eg, a pharmacologically active ingredient or a marker suitable substance if such an ingredient is unknown).
Once the dilemma of standardization is solved, herbal medicines are scrutinized in much the same way as other drugs. The literature contains several randomized, clinical trials and systematic reviews/meta-analyses of these studies.3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books recently were published.3-6
Unfortunately, systematic reviews are often limited by the paucity and varied methodological quality of the primary studies,3,7 and research funds are generally scarce, in part because plants cannot be patented.
Generalizations about the efficacy of herbal medicines are not possible. Each remedy must be judged on its own merits. Some herbal products have demon strated efficacy for certain conditions, while others have not. Overall, few products have been subjected to extensive clinical testing.3
The bottom line? As a review in the New England Journal of Medicine concluded, “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy.”7
Tradition is no guarantee, as in the case of kava
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can cause both desirable and undesirable effects. TABLE 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries, apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic agent,9 but it was recently associated with several cases of serious liver damage.10 As a result, it was withdrawn from the markets of several European countries, and the US Food and Drug Administration (FDA) has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines can interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence would be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) are contaminated with heavy metals13; contain misidentified, toxic herbal ingredients14; or are adulterated with prescription drugs.15 Be sure an herbal medication cannot cause harm before prescribing or recommending it.
TABLE 3
7 herbal medicines associated with serious adverse effects*
| COMMON (LATIN) NAME | INDICATION | ADVERSE EFFECTS (EXAMPLES) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribed drugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| * This is a sampling only. Also, without positive safety data, herbal medications cannot be considered safe for pregnant or nursing women. | ||
Uneven quality marks herbal medicines
The quality of an herbal preparation contributes to its efficacy and safety. Herbal dietary supplements usually are unregulated as drugs and can vary widely in quality—to the point of being ineffective.7,16
In the United States, herbal preparations must meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus, they are marketed without FDA approval of their efficacy and safety. The DSHEA prohibits companies from making medical claims for dietary supplements, but does allow structure or functional claims. If safety concerns arise, the burden of proof lies not with the manufacturer, but with the FDA.
Many experts believe this regulation is insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon require efficacy to be based on bibliographic data, and safety will be governed as it is with conventional drugs.17
Not enough data to base decisions on cost
As a general rule, clinicians should try to recommend treatments that save money for patients and the health-care system. Although herbal medications are relatively inexpensive, few proper economic analyses exist.18,19 So far, only 1 cost evaluation20 of an herbal medicine has been published. This study involved treatment of symptomatic chronic venous insufficiency and compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds; the treatments were comparable.
For the prescribing physician, this means decisions cannot be based on conclusive cost-analyses. Until such studies are available, decisions must be informed by our knowledge of the efficacy, safety, and quality of herbal medications.
One of 5 Ayurvedic herbal medicine products may contain potentially toxic levels of lead, mercury, and/or arsenic, according to a study in the December 15 issue of JAMA. The Ayurvedic tradition is a holistic healing system that originated in India. When researchers tested Ayurvedic products produced in South Asia and sold in the Boston area, 14 of 70 contained heavy metals. If taken according to the package directions, the preparations would exceed published standards for the metals, some of them by a huge margin.
Pharmaceuticals in an herbal remedy?
Among other hazards detected in herbal products are undeclared prescription drugs mixed into the ingredients of some Chinese preparations, according to the FDA. And last May, Consumer Reports identified 12 dietary supplements “too dangerous to be on the market,” yet all were readily available in stores or online. They include comfrey, androstenedione, chaparral, and kava.
Pose the question
All the more reason to ask patients what products they may be using. Ask specifically about herbal or natural remedies, since many people do not consider them drugs and fail to disclose them to physicians.
—The editors
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA. 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram. 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med. 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol. 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed. 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci. 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg. 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther. 2001;70:497-504.
14. Nortier JL, Martinez MC. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med. 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA. 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia. 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Kernick DE, ed. Getting Health Economics into Practice. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeconomics. 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag. 1997;2:86-91.
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA. 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram. 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med. 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol. 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed. 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci. 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg. 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther. 2001;70:497-504.
14. Nortier JL, Martinez MC. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med. 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA. 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia. 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Kernick DE, ed. Getting Health Economics into Practice. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeconomics. 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag. 1997;2:86-91.
Metabolic syndrome: When and how to intervene
- First-line therapies for both lipid and nonlipid risk factors? Weight loss and regular exercise.
- Reduce low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL when metabolic syndrome is present.
- Lower the total of LDL and very-low-density lipoprotein (VLDL) cholesterol to less than 130 mg/dL, especially in patients with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides.
- When drug intervention is needed to lower non-HDL cholesterol, use an LDL-lowering drug or add nicotinic acid or fibrate to reduce VLDL.
This risk are serious. Metabolic syndrome amplifies morbidity and mortality due to diabetes mellitus and cardiovascular disease to such an extent that the National Cholesterol Education Program identifies it as a critical target of risk reduction, second only to reducing low-density lipoprotein (LDL) cholesterol.2
In our primary care capacity, Ob/Gyns are likely to be the first to identify metabolic syndrome and intervene—and intervention makes a difference. An aggressive approach to lipid lowering is critical. However, solid evidence confirms that weight loss and physical activity eliminate some or all of the risk factors in many patients. There’s the challenge. Notably, research reported in theNew England Journal of Medicine found that, with a nutritionist’s guidance, many patients who were counseled about these lifestyle changes reduced their risk of type 2 diabetes by 58% over 3 years.3
This article reviews key studies linking metabolic syndrome to heart disease, diabetes, and death; and describes diagnostic and management fundamentals.
What defines metabolic syndrome?
Women with 3 or more of these factors have metabolic syndrome:
- Abdominal obesity; ie, waist circumference exceeding 35 inches (88 cm).
- Triglyceride level of 150 mg/dL or more.
- High-density lipoprotein (HDL) cholesterol below 50 mg/dL.
- Blood pressure 130/85 mm Hg or above.
- Fasting glucose of 100 mg/dL or above.2
Women being treated for hypertension or diabetes can be presumed to meet the criteria for those components of metabolic syndrome.
Though the syndrome affects men and women equally overall, Hispanic and African-American women have a 26% and 57% higher incidence, respectively, than men of the same ethnic and racial background.1
Obesity and age drive full-blown syndrome
Insulin resistance, dyslipidemia, and other components of metabolic syndrome exist because of intrinsic genetic susceptibility, which occurs to varying degrees throughout the population.
Some conditions cause this genetic susceptibility to blossom into the full-blown syndrome. Obesity is the driving force for much of this expression.
Age is a highly important factor. Prevalence of metabolic syndrome climbs sharply above the age of 40—in both men and women—so much so that the syndrome is close to becoming the common feature for older age groups (FIGURE 1).
Studies find link to diabetes, cardiovascular disease
What evidence do we have that this syndrome is associated with an increased risk of diabetes, heart disease, and death?
In a study of slightly more than 1,000 males with 10 years of follow-up, Lakka et al4 found a 3.5-fold increased risk of cardiovascular disease mortality with metabolic syndrome. This risk is as high as or higher than the risk for cardiovascular disease in men with type 2 diabetes, which has been described in many other studies.
Risk rises with number of components
A more recent study explored the impact of the number of components of metabolic syndrome present.5 After controlling for age, family history of diabetes, alcohol intake, and cigarette smoking, investigators found a multivariate-adjusted relative risk of cardiovascular disease, compared with an absence of components, of 3.18, 3.48, 12.55, and 14.15 (P<.001 for the presence of and or more components respectively. corresponding relative risks type diabetes were>P<.001>
Another recent study used the coronary artery calcium score as a surrogate for cardiovascular disease.6 This measure is increasingly recognized as a marker of underlying atherosclerosis. In both men and women, the amount of calcium in the coronary arteries increased with the number of metabolic syndrome components.
Dyslipidemia is a critical component
Several studies have identified dyslipidemia as the key component of metabolic syndrome. That is not to say that other components are unimportant—only that lipid abnormalities appear to have the greatest impact.
In a trial from the Third National Health and Nutrition Examination Study (NHANES III),7 the large dataset that has been studied extensively for this disorder, low HDL cholesterol and high blood pressure in the presence of overt diabetes appeared to account for much of the excess risk associated with metabolic syndrome. In fact, blood pressure, HDL cholesterol, and diabetes—but not metabolic syndrome per se—were significant multivariate predictors of prevalent CHD.7
Twice the risk of myocardial infarction and stroke
Another recent study8 found twice the risk of myocardial infarction and stroke when metabolic syndrome was present.
Investigators used logistic regression to estimate the association of the syndrome as a whole and each of its 5 component conditions separately with a history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke).
Metabolic syndrome was significantly related in multivariate analysis to MI (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57).
Among the 5 component conditions of metabolic syndrome, the following were independently and significantly related to MI/stroke8:
- insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66),
- low HDL cholesterol (OR, 1.35; 95% CI, 1.05 to 1.74),
- hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and
- high triglycerides (OR, 1.66; 95% CI, 1.20 to 2.30).
With nutritionist counseling, glucose-impaired patients lost weight
Can lifestyle adjustments alone prevent type 2 diabetes to any great extent? Can anything be done to get overweight patients with impaired glucose to stick to a diet and exercise regimen?
Yes to both questions, according to researchers who conducted a randomized, controlled trial3 of lifestyle changes among 522 middle-aged, overweight men (n = 172) and women (n = 350) with impaired glucose tolerance and a mean body mass index of 31.
Chief intervention was nutritionist counseling
Nevertheless, getting the study participants to live healthier was a complex undertaking. The intervention group received individualized counseling to encourage them to:
- reduce their weight by 5% or more
- reduce fat consumption to less than 30%
- limit saturated fat intake to less than 10%
- eat 15 g or more of fiber per 1,000 kcal of intake
- exercise moderately for at least 30 minutes daily
- eat whole-grain products, fruits and vegetables, low-fat dairy products and meat, and vegetable oils rich in monounsaturated fatty acids.
Each person in the intervention group met with a nutritionist 7 times during the first year of the study and every 3 months thereafter. Dietary advice was based on 3-day diaries of food intake, completed quarterly.
Endurance exercise was recommended to increase aerobic capacity and improve cardiorespiratory function. In addition, progressive, individually tailored, circuit-type resistance training was offered to improve muscle strength. During the first year of the study, the rate of participation in these resistance training sessions ranged from 50% to 85%.
A very different picture for controls
In contrast to the individualized attention focused on the intervention group, controls received general oral and written information about diet and exercise at the beginning of the trial and at each annual visit, but no detailed counseling. They also completed a 3-day food diary at the beginning of the study and at each annual visit.
Risk of type 2 diabetes 58% lower
The percentage of patients in the intervention group who achieved a particular goal ranged from 25% (fiber consumption) to 86% (exercise). Net weight loss at the end of the second year was 3.5 ± 5.5 kg in the intervention group versus 0.8 ± 4.4 kg in the control group (P<.001 for both comparisons>
While this weight loss was not dramatic, the differences between groups was substantial. For example, individuals who lost at least 5% of their baseline weight had an odds ratio for diabetes of 0.3 (95 percent confidence interval, 0.1 to 0.7).
Over the duration of the trial, the cumulative incidence of type 2 diabetes was 58% lower in the intervention group than in the control group (P<.001>3 When women were singled out, the incidence of diabetes was 54% lower in the intervention group than among controls.
The failure to make any changes in lifestyle led to an incidence of diabetes very near the 35% estimate for this high-risk population.
Patients willingly stuck to diet, exercise
The dropout rate was low, and the researchers concluded that patients with impaired glucose tolerance are “willing and able to participate in a demanding intervention program if it is made available to them.”13
Unique lipid triad
High triglycerides, small LDL particles, and low HDL form the characteristic lipid profile of women with metabolic syndrome. For classification of the different levels of cholesterol, see TABLE 1.
High triglycerides heighten risk. High triglyceride levels carry an increased, independent risk of cardiovascular disease, particularly in women. As levels exceed 200 mg/dL, that risk rises sharply (FIGURE 2).9 Other studies, including a metaanalysis, have confirmed this finding.
Low HDL cholesterol is another independent risk factor for cardiovascular disease— one that is independent of standard risk markers such as LDL cholesterol. At high total cholesterol levels, the risk of cardiovascular disease increases, but that risk is even higher when HDL is low.10
Small LDL cholesterol particles. The characteristic LDL abnormality in patients with metabolic syndrome is not elevated levels, but a shift in size from larger to smaller LDL particles. In fact, the cardiovascular disease risk associated with small LDL particles is several times higher than the risk associated with the larger particles.
Smaller particles are more atherogenic than larger LDL particles despite their lower cholesterol content. The reasons:
They are cleared more slowly from plasma, taken up more readily by the artery wall, and more actively retained.
They are more rapidly oxidized, an important step in the atherogenic process.
At any level of LDL, there are more particles circulating.
Individuals tend to cluster into 2 groups based on LDL particle size: those with larger LDL particles, who usually have relatively lower triglyceride levels, and those with smaller LDL particles, who tend to have higher triglycerides. At triglyceride levels above 150 mg/dL—the cutoff for metabolic syndrome—individuals are more likely to have smaller LDL particles.
What is the risk associated with smaller particles? A study from 2001 by St. Pierre and colleagues11 showed that, at any level of triglycerides, LDL cholesterol, or apolipoprotein B (another LDL-related risk marker), the risk of coronary heart disease associated with small LDL particles is more than 3 times the risk associated with larger LDL particles.
TABLE 1
ATP III classification of LDL, total, and HDL cholesterol (mg/dL)
| LEVEL | STATUS |
|---|---|
| LDL cholesterol | |
| Optimal | |
| 100–129 | Near or above optimal |
| 130–159 | Borderline high |
| 160 –189 | High |
| ≥190 | Very high |
| Total cholesterol | |
| Desirable | |
| 200–239 | Borderline high |
| ≥240 | High |
| HDL cholesterol | |
| Low | |
| ≥60 | High |
| LDL = low-density lipoprotein | |
| HDL = high-density lipoprotein | |
| Source: NCEP.2 Reprinted with permission | |
C-reactive protein is an important marker
C-reactive protein is an important marker of the inflammation linked to heart disease. Elevated C-reactive protein also is associated with insulin resistance and adiposity. The trigger for the liver’s production of C-reactive protein is a cytokine released in large part by adipose tissue and endothelial cells.
Because a standardized, highly sensitive assay to measure plasma C-reactive protein is now available, there is a movement to include it in the definition of metabolic syndrome. As a recent study shows, the level of C-reactive protein rises with the number of components of metabolic syndrome.12 Levels tend to be higher in women than in men.
In addition, as Ridker et al13 and others have shown, as the levels of C-reactive protein rise from low (3 mg/L), so does the risk of cardiovascular disease.
Moreover, high C-reactive protein levels add to the risk associated with standard cholesterol-based risk factors. Thus, adding plasma C-reactive protein to standard lipid screening may help predict the risk of cardiovascular disease in women with high as well as low cholesterol levels.13 For example, if an individual has both elevated C-reactive protein and the metabolic syndrome, the relative risk of cardiovascular disease is more than twice the risk in women with high C-reactive protein alone.
First-line therapies are weight loss, exercise
According to ATP III2, the aims of managing metabolic syndrome are:
- to reduce causes of the syndrome, such as obesity and inactivity, and
- to treat lipid and nonlipid risk factors.
Weight loss enhances efforts to lower LDL cholesterol and reduces the impact of all risk factors for metabolic syndrome.2
Physical activity can reduce the risk of cardiovascular disease by improving cardiovascular fitness and coronary blood flow. Regular physical activity reduces very-lowdensity lipoprotein (VLDL) cholesterol levels, increases HDL cholesterol, and can lower LDL levels in some individuals. It also may help reduce blood pressure and insulin resistance.
ATP III recommends regular physical activity as a key component of managing high serum cholesterol.2 For more information on these interventions, see “Integrating evidence and experience”.
Why aggressive lipid lowering?
The current goal is reducing LDL cholesterol to less than 100 mg/dL when metabolic syndrome is present. Even lower levels, eg, less than 70 mg/dL, may be advisable when both cardiovascular disease and metabolic syndrome are present.14
A broader measure of atherogenic lipoproteins is total cholesterol minus HDL cholesterol. This measure incorporates some of the triglyceride-rich lipoproteins involved in atherosclerosis. The target is less than 130 mg/dL (TABLE 2).2 All people with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides should be managed to achieve this goal. Weight reduction and physical activity are critical, even with drug therapy.
TABLE 2
Comparison of LDL and non-HDL cholesterol goals for 3 risk categories
| RISK CATEGORY | LDL GOAL (MG/DL) | NON-HDL GOAL (MG/DL) |
|---|---|---|
| Coronary heart disease or risk equivalent (10-year risk for coronary heart disease >20%) | ||
| 2 or more risk factors and 10-year risk 20% | ||
| 0–1 risk factor | ||
| LDL = low-density lipoprotein | ||
| HDL = high-density lipoprotein | ||
| Source: NCEP.2 Reprinted with permission | ||
When to use drug therapy
Pharmacologic intervention to lower non-HDL cholesterol may involve use of an LDL-lowering drug or the addition of nicotinic acid or fibrate to reduce VLDL.
When triglyceride levels are extremely high (500 mg/dL or higher), the primary goal of therapy is preventing acute pancreatitis. This may require a combination of low-fat diet, weight loss, regular physical activity, and a triglyceride-lowering drug.2 Once triglyceride levels decline to less than 500 mg/dL, the emphasis can return to reducing cardiovascular risk.
When LDL cholesterol is very high. LDL cholesterol levels of 190 mg/dL or higher, usually signify genetic hypercholesterolemia.2 Early detection—preferably, in young adults—is crucial to prevent coronary heart disease, and a combination of drugs usually is necessary to reduce LDL cholesterol levels. Otherwise, aim for the goals in TABLE 2.
Benefits of statins. In a post hoc analysis of data from the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol and coronary heart disease, those with the triad of elevated LDL cholesterol, low HDL cholesterol, and elevated triglycerides were more likely than patients with isolated high LDL cholesterol to have other characteristics of the metabolic syndrome. They also had a greater risk of coronary heart disease on placebo and received greater benefit with simvastatin therapy.15
Fibrates and HDL cholesterol. In a subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, investigators explored the efficacy of gemfibrozil in men with coronary heart disease, HDL cholesterol levels of 40 mg/dL or below, and LDL cholesterol of 140 mg/dL or less.16
Participants were given 1,200 mg of gemfibrozil daily and followed for an average of 5.1 years. The drug was most effective in those with diabetes, reducing death from coronary heart disease by 41% (hazard ratio, 0.59; 95% confidence interval, 0.39–0.91; P<.02>
Among men without diabetes, gemfibrozil was most effective for those in the highest quartile for fasting plasma insulin (risk reduction 35%; P<.04>
Among those who had coronary heart disease and low HDL cholesterol, the drug reduced major cardiovascular events.
Nicotinic acid improves each of the common lipid abnormalities found in metabolic syndrome.17 Early concern that it can precipitate or worsen diabetes has largely been disproved, although some data suggest that it can slightly aggravate insulin resistance and elevate blood glucose.
When it comes to cognitive function, is metabolic syndrome a “brain drain”?
A recent prospective observational study14 found a link between metabolic syndrome and cognitive impairment in the elderly, particularly when inflammation also was present.
Hypertension, diabetes, and other cardiovascular and metabolic risk factors are thought to play a role in the development of Alzheimer’s disease and vascular dementia.
Researchers followed 2,632 elderly men and women over 5 years (mean age: 74), documenting metabolic syndrome in 1,016. Those with metabolic syndrome were more likely to have cognitive impairment (26% versus 21%; multivariate-adjusted relative risk [RR], 1.20; 95% confidence interval [CI], 1.02–1.41) than were those without the syndrome.
Investigators also documented high inflammation in the study population, defining it as higher-than-median serum levels of both interleukin 6 (≥2 pg/mL) and C-reactive protein (≥2 mg/L). They then assessed its relationship to cognitive decline.
Those with both metabolic syndrome and high inflammation had an increased likelihood of cognitive impairment, compared with those without metabolic syndrome (multivariate-adjusted RR, 1.66; 95% CI, 1.19–2.32).
Those with metabolic syndrome and low inflammation had a low likelihood of impairment (multivariate-adjusted RR, 1.08; 95% CI, 0.89–1.30).
These findings held true even after adjusting for demographics, comorbidities, and health habits. It remains to be seen whether attempts to prevent metabolic syndrome or lower inflammation also limit cognitive impairment.
1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Examination Study. JAMA. 2002;287:356-359.
2. Expert Panel on Detection. Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
4. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.
5. Nakanishi N, Takatorige T, Fukuda H, et al. Components of the metabolic syndrome as predictors of cardiovascular disease and type 2 diabetes in middle-aged Japanese men. Diabetes Res Clin Pract. 2004;64:59-70.
6. Reilly MP, Wolfe ML, Rhodes T, et al. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation. 2004;110:803-809.
7. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.
8. Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109:42-46.
9. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H.
10. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256:2835-2838.
11. St. Pierre, et al. Circulation. 2001;104:2295.-
12. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380-385.
13. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813-1818.
14. Yaffe K, Kamaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237-2242.
15. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.
16. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs highdensity lipoprotein intervention trial (VA-HIT). Arch Intern Med. 2002;162:2597-2604.
17. Meyers CD, Kashyap ML. Management of the metabolic syndrome—nicotinic acid. Endocrinol Metab Clin North Am. 2004;33:557-575.
- First-line therapies for both lipid and nonlipid risk factors? Weight loss and regular exercise.
- Reduce low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL when metabolic syndrome is present.
- Lower the total of LDL and very-low-density lipoprotein (VLDL) cholesterol to less than 130 mg/dL, especially in patients with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides.
- When drug intervention is needed to lower non-HDL cholesterol, use an LDL-lowering drug or add nicotinic acid or fibrate to reduce VLDL.
This risk are serious. Metabolic syndrome amplifies morbidity and mortality due to diabetes mellitus and cardiovascular disease to such an extent that the National Cholesterol Education Program identifies it as a critical target of risk reduction, second only to reducing low-density lipoprotein (LDL) cholesterol.2
In our primary care capacity, Ob/Gyns are likely to be the first to identify metabolic syndrome and intervene—and intervention makes a difference. An aggressive approach to lipid lowering is critical. However, solid evidence confirms that weight loss and physical activity eliminate some or all of the risk factors in many patients. There’s the challenge. Notably, research reported in theNew England Journal of Medicine found that, with a nutritionist’s guidance, many patients who were counseled about these lifestyle changes reduced their risk of type 2 diabetes by 58% over 3 years.3
This article reviews key studies linking metabolic syndrome to heart disease, diabetes, and death; and describes diagnostic and management fundamentals.
What defines metabolic syndrome?
Women with 3 or more of these factors have metabolic syndrome:
- Abdominal obesity; ie, waist circumference exceeding 35 inches (88 cm).
- Triglyceride level of 150 mg/dL or more.
- High-density lipoprotein (HDL) cholesterol below 50 mg/dL.
- Blood pressure 130/85 mm Hg or above.
- Fasting glucose of 100 mg/dL or above.2
Women being treated for hypertension or diabetes can be presumed to meet the criteria for those components of metabolic syndrome.
Though the syndrome affects men and women equally overall, Hispanic and African-American women have a 26% and 57% higher incidence, respectively, than men of the same ethnic and racial background.1
Obesity and age drive full-blown syndrome
Insulin resistance, dyslipidemia, and other components of metabolic syndrome exist because of intrinsic genetic susceptibility, which occurs to varying degrees throughout the population.
Some conditions cause this genetic susceptibility to blossom into the full-blown syndrome. Obesity is the driving force for much of this expression.
Age is a highly important factor. Prevalence of metabolic syndrome climbs sharply above the age of 40—in both men and women—so much so that the syndrome is close to becoming the common feature for older age groups (FIGURE 1).
Studies find link to diabetes, cardiovascular disease
What evidence do we have that this syndrome is associated with an increased risk of diabetes, heart disease, and death?
In a study of slightly more than 1,000 males with 10 years of follow-up, Lakka et al4 found a 3.5-fold increased risk of cardiovascular disease mortality with metabolic syndrome. This risk is as high as or higher than the risk for cardiovascular disease in men with type 2 diabetes, which has been described in many other studies.
Risk rises with number of components
A more recent study explored the impact of the number of components of metabolic syndrome present.5 After controlling for age, family history of diabetes, alcohol intake, and cigarette smoking, investigators found a multivariate-adjusted relative risk of cardiovascular disease, compared with an absence of components, of 3.18, 3.48, 12.55, and 14.15 (P<.001 for the presence of and or more components respectively. corresponding relative risks type diabetes were>P<.001>
Another recent study used the coronary artery calcium score as a surrogate for cardiovascular disease.6 This measure is increasingly recognized as a marker of underlying atherosclerosis. In both men and women, the amount of calcium in the coronary arteries increased with the number of metabolic syndrome components.
Dyslipidemia is a critical component
Several studies have identified dyslipidemia as the key component of metabolic syndrome. That is not to say that other components are unimportant—only that lipid abnormalities appear to have the greatest impact.
In a trial from the Third National Health and Nutrition Examination Study (NHANES III),7 the large dataset that has been studied extensively for this disorder, low HDL cholesterol and high blood pressure in the presence of overt diabetes appeared to account for much of the excess risk associated with metabolic syndrome. In fact, blood pressure, HDL cholesterol, and diabetes—but not metabolic syndrome per se—were significant multivariate predictors of prevalent CHD.7
Twice the risk of myocardial infarction and stroke
Another recent study8 found twice the risk of myocardial infarction and stroke when metabolic syndrome was present.
Investigators used logistic regression to estimate the association of the syndrome as a whole and each of its 5 component conditions separately with a history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke).
Metabolic syndrome was significantly related in multivariate analysis to MI (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57).
Among the 5 component conditions of metabolic syndrome, the following were independently and significantly related to MI/stroke8:
- insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66),
- low HDL cholesterol (OR, 1.35; 95% CI, 1.05 to 1.74),
- hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and
- high triglycerides (OR, 1.66; 95% CI, 1.20 to 2.30).
With nutritionist counseling, glucose-impaired patients lost weight
Can lifestyle adjustments alone prevent type 2 diabetes to any great extent? Can anything be done to get overweight patients with impaired glucose to stick to a diet and exercise regimen?
Yes to both questions, according to researchers who conducted a randomized, controlled trial3 of lifestyle changes among 522 middle-aged, overweight men (n = 172) and women (n = 350) with impaired glucose tolerance and a mean body mass index of 31.
Chief intervention was nutritionist counseling
Nevertheless, getting the study participants to live healthier was a complex undertaking. The intervention group received individualized counseling to encourage them to:
- reduce their weight by 5% or more
- reduce fat consumption to less than 30%
- limit saturated fat intake to less than 10%
- eat 15 g or more of fiber per 1,000 kcal of intake
- exercise moderately for at least 30 minutes daily
- eat whole-grain products, fruits and vegetables, low-fat dairy products and meat, and vegetable oils rich in monounsaturated fatty acids.
Each person in the intervention group met with a nutritionist 7 times during the first year of the study and every 3 months thereafter. Dietary advice was based on 3-day diaries of food intake, completed quarterly.
Endurance exercise was recommended to increase aerobic capacity and improve cardiorespiratory function. In addition, progressive, individually tailored, circuit-type resistance training was offered to improve muscle strength. During the first year of the study, the rate of participation in these resistance training sessions ranged from 50% to 85%.
A very different picture for controls
In contrast to the individualized attention focused on the intervention group, controls received general oral and written information about diet and exercise at the beginning of the trial and at each annual visit, but no detailed counseling. They also completed a 3-day food diary at the beginning of the study and at each annual visit.
Risk of type 2 diabetes 58% lower
The percentage of patients in the intervention group who achieved a particular goal ranged from 25% (fiber consumption) to 86% (exercise). Net weight loss at the end of the second year was 3.5 ± 5.5 kg in the intervention group versus 0.8 ± 4.4 kg in the control group (P<.001 for both comparisons>
While this weight loss was not dramatic, the differences between groups was substantial. For example, individuals who lost at least 5% of their baseline weight had an odds ratio for diabetes of 0.3 (95 percent confidence interval, 0.1 to 0.7).
Over the duration of the trial, the cumulative incidence of type 2 diabetes was 58% lower in the intervention group than in the control group (P<.001>3 When women were singled out, the incidence of diabetes was 54% lower in the intervention group than among controls.
The failure to make any changes in lifestyle led to an incidence of diabetes very near the 35% estimate for this high-risk population.
Patients willingly stuck to diet, exercise
The dropout rate was low, and the researchers concluded that patients with impaired glucose tolerance are “willing and able to participate in a demanding intervention program if it is made available to them.”13
Unique lipid triad
High triglycerides, small LDL particles, and low HDL form the characteristic lipid profile of women with metabolic syndrome. For classification of the different levels of cholesterol, see TABLE 1.
High triglycerides heighten risk. High triglyceride levels carry an increased, independent risk of cardiovascular disease, particularly in women. As levels exceed 200 mg/dL, that risk rises sharply (FIGURE 2).9 Other studies, including a metaanalysis, have confirmed this finding.
Low HDL cholesterol is another independent risk factor for cardiovascular disease— one that is independent of standard risk markers such as LDL cholesterol. At high total cholesterol levels, the risk of cardiovascular disease increases, but that risk is even higher when HDL is low.10
Small LDL cholesterol particles. The characteristic LDL abnormality in patients with metabolic syndrome is not elevated levels, but a shift in size from larger to smaller LDL particles. In fact, the cardiovascular disease risk associated with small LDL particles is several times higher than the risk associated with the larger particles.
Smaller particles are more atherogenic than larger LDL particles despite their lower cholesterol content. The reasons:
They are cleared more slowly from plasma, taken up more readily by the artery wall, and more actively retained.
They are more rapidly oxidized, an important step in the atherogenic process.
At any level of LDL, there are more particles circulating.
Individuals tend to cluster into 2 groups based on LDL particle size: those with larger LDL particles, who usually have relatively lower triglyceride levels, and those with smaller LDL particles, who tend to have higher triglycerides. At triglyceride levels above 150 mg/dL—the cutoff for metabolic syndrome—individuals are more likely to have smaller LDL particles.
What is the risk associated with smaller particles? A study from 2001 by St. Pierre and colleagues11 showed that, at any level of triglycerides, LDL cholesterol, or apolipoprotein B (another LDL-related risk marker), the risk of coronary heart disease associated with small LDL particles is more than 3 times the risk associated with larger LDL particles.
TABLE 1
ATP III classification of LDL, total, and HDL cholesterol (mg/dL)
| LEVEL | STATUS |
|---|---|
| LDL cholesterol | |
| Optimal | |
| 100–129 | Near or above optimal |
| 130–159 | Borderline high |
| 160 –189 | High |
| ≥190 | Very high |
| Total cholesterol | |
| Desirable | |
| 200–239 | Borderline high |
| ≥240 | High |
| HDL cholesterol | |
| Low | |
| ≥60 | High |
| LDL = low-density lipoprotein | |
| HDL = high-density lipoprotein | |
| Source: NCEP.2 Reprinted with permission | |
C-reactive protein is an important marker
C-reactive protein is an important marker of the inflammation linked to heart disease. Elevated C-reactive protein also is associated with insulin resistance and adiposity. The trigger for the liver’s production of C-reactive protein is a cytokine released in large part by adipose tissue and endothelial cells.
Because a standardized, highly sensitive assay to measure plasma C-reactive protein is now available, there is a movement to include it in the definition of metabolic syndrome. As a recent study shows, the level of C-reactive protein rises with the number of components of metabolic syndrome.12 Levels tend to be higher in women than in men.
In addition, as Ridker et al13 and others have shown, as the levels of C-reactive protein rise from low (3 mg/L), so does the risk of cardiovascular disease.
Moreover, high C-reactive protein levels add to the risk associated with standard cholesterol-based risk factors. Thus, adding plasma C-reactive protein to standard lipid screening may help predict the risk of cardiovascular disease in women with high as well as low cholesterol levels.13 For example, if an individual has both elevated C-reactive protein and the metabolic syndrome, the relative risk of cardiovascular disease is more than twice the risk in women with high C-reactive protein alone.
First-line therapies are weight loss, exercise
According to ATP III2, the aims of managing metabolic syndrome are:
- to reduce causes of the syndrome, such as obesity and inactivity, and
- to treat lipid and nonlipid risk factors.
Weight loss enhances efforts to lower LDL cholesterol and reduces the impact of all risk factors for metabolic syndrome.2
Physical activity can reduce the risk of cardiovascular disease by improving cardiovascular fitness and coronary blood flow. Regular physical activity reduces very-lowdensity lipoprotein (VLDL) cholesterol levels, increases HDL cholesterol, and can lower LDL levels in some individuals. It also may help reduce blood pressure and insulin resistance.
ATP III recommends regular physical activity as a key component of managing high serum cholesterol.2 For more information on these interventions, see “Integrating evidence and experience”.
Why aggressive lipid lowering?
The current goal is reducing LDL cholesterol to less than 100 mg/dL when metabolic syndrome is present. Even lower levels, eg, less than 70 mg/dL, may be advisable when both cardiovascular disease and metabolic syndrome are present.14
A broader measure of atherogenic lipoproteins is total cholesterol minus HDL cholesterol. This measure incorporates some of the triglyceride-rich lipoproteins involved in atherosclerosis. The target is less than 130 mg/dL (TABLE 2).2 All people with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides should be managed to achieve this goal. Weight reduction and physical activity are critical, even with drug therapy.
TABLE 2
Comparison of LDL and non-HDL cholesterol goals for 3 risk categories
| RISK CATEGORY | LDL GOAL (MG/DL) | NON-HDL GOAL (MG/DL) |
|---|---|---|
| Coronary heart disease or risk equivalent (10-year risk for coronary heart disease >20%) | ||
| 2 or more risk factors and 10-year risk 20% | ||
| 0–1 risk factor | ||
| LDL = low-density lipoprotein | ||
| HDL = high-density lipoprotein | ||
| Source: NCEP.2 Reprinted with permission | ||
When to use drug therapy
Pharmacologic intervention to lower non-HDL cholesterol may involve use of an LDL-lowering drug or the addition of nicotinic acid or fibrate to reduce VLDL.
When triglyceride levels are extremely high (500 mg/dL or higher), the primary goal of therapy is preventing acute pancreatitis. This may require a combination of low-fat diet, weight loss, regular physical activity, and a triglyceride-lowering drug.2 Once triglyceride levels decline to less than 500 mg/dL, the emphasis can return to reducing cardiovascular risk.
When LDL cholesterol is very high. LDL cholesterol levels of 190 mg/dL or higher, usually signify genetic hypercholesterolemia.2 Early detection—preferably, in young adults—is crucial to prevent coronary heart disease, and a combination of drugs usually is necessary to reduce LDL cholesterol levels. Otherwise, aim for the goals in TABLE 2.
Benefits of statins. In a post hoc analysis of data from the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol and coronary heart disease, those with the triad of elevated LDL cholesterol, low HDL cholesterol, and elevated triglycerides were more likely than patients with isolated high LDL cholesterol to have other characteristics of the metabolic syndrome. They also had a greater risk of coronary heart disease on placebo and received greater benefit with simvastatin therapy.15
Fibrates and HDL cholesterol. In a subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, investigators explored the efficacy of gemfibrozil in men with coronary heart disease, HDL cholesterol levels of 40 mg/dL or below, and LDL cholesterol of 140 mg/dL or less.16
Participants were given 1,200 mg of gemfibrozil daily and followed for an average of 5.1 years. The drug was most effective in those with diabetes, reducing death from coronary heart disease by 41% (hazard ratio, 0.59; 95% confidence interval, 0.39–0.91; P<.02>
Among men without diabetes, gemfibrozil was most effective for those in the highest quartile for fasting plasma insulin (risk reduction 35%; P<.04>
Among those who had coronary heart disease and low HDL cholesterol, the drug reduced major cardiovascular events.
Nicotinic acid improves each of the common lipid abnormalities found in metabolic syndrome.17 Early concern that it can precipitate or worsen diabetes has largely been disproved, although some data suggest that it can slightly aggravate insulin resistance and elevate blood glucose.
When it comes to cognitive function, is metabolic syndrome a “brain drain”?
A recent prospective observational study14 found a link between metabolic syndrome and cognitive impairment in the elderly, particularly when inflammation also was present.
Hypertension, diabetes, and other cardiovascular and metabolic risk factors are thought to play a role in the development of Alzheimer’s disease and vascular dementia.
Researchers followed 2,632 elderly men and women over 5 years (mean age: 74), documenting metabolic syndrome in 1,016. Those with metabolic syndrome were more likely to have cognitive impairment (26% versus 21%; multivariate-adjusted relative risk [RR], 1.20; 95% confidence interval [CI], 1.02–1.41) than were those without the syndrome.
Investigators also documented high inflammation in the study population, defining it as higher-than-median serum levels of both interleukin 6 (≥2 pg/mL) and C-reactive protein (≥2 mg/L). They then assessed its relationship to cognitive decline.
Those with both metabolic syndrome and high inflammation had an increased likelihood of cognitive impairment, compared with those without metabolic syndrome (multivariate-adjusted RR, 1.66; 95% CI, 1.19–2.32).
Those with metabolic syndrome and low inflammation had a low likelihood of impairment (multivariate-adjusted RR, 1.08; 95% CI, 0.89–1.30).
These findings held true even after adjusting for demographics, comorbidities, and health habits. It remains to be seen whether attempts to prevent metabolic syndrome or lower inflammation also limit cognitive impairment.
- First-line therapies for both lipid and nonlipid risk factors? Weight loss and regular exercise.
- Reduce low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL when metabolic syndrome is present.
- Lower the total of LDL and very-low-density lipoprotein (VLDL) cholesterol to less than 130 mg/dL, especially in patients with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides.
- When drug intervention is needed to lower non-HDL cholesterol, use an LDL-lowering drug or add nicotinic acid or fibrate to reduce VLDL.
This risk are serious. Metabolic syndrome amplifies morbidity and mortality due to diabetes mellitus and cardiovascular disease to such an extent that the National Cholesterol Education Program identifies it as a critical target of risk reduction, second only to reducing low-density lipoprotein (LDL) cholesterol.2
In our primary care capacity, Ob/Gyns are likely to be the first to identify metabolic syndrome and intervene—and intervention makes a difference. An aggressive approach to lipid lowering is critical. However, solid evidence confirms that weight loss and physical activity eliminate some or all of the risk factors in many patients. There’s the challenge. Notably, research reported in theNew England Journal of Medicine found that, with a nutritionist’s guidance, many patients who were counseled about these lifestyle changes reduced their risk of type 2 diabetes by 58% over 3 years.3
This article reviews key studies linking metabolic syndrome to heart disease, diabetes, and death; and describes diagnostic and management fundamentals.
What defines metabolic syndrome?
Women with 3 or more of these factors have metabolic syndrome:
- Abdominal obesity; ie, waist circumference exceeding 35 inches (88 cm).
- Triglyceride level of 150 mg/dL or more.
- High-density lipoprotein (HDL) cholesterol below 50 mg/dL.
- Blood pressure 130/85 mm Hg or above.
- Fasting glucose of 100 mg/dL or above.2
Women being treated for hypertension or diabetes can be presumed to meet the criteria for those components of metabolic syndrome.
Though the syndrome affects men and women equally overall, Hispanic and African-American women have a 26% and 57% higher incidence, respectively, than men of the same ethnic and racial background.1
Obesity and age drive full-blown syndrome
Insulin resistance, dyslipidemia, and other components of metabolic syndrome exist because of intrinsic genetic susceptibility, which occurs to varying degrees throughout the population.
Some conditions cause this genetic susceptibility to blossom into the full-blown syndrome. Obesity is the driving force for much of this expression.
Age is a highly important factor. Prevalence of metabolic syndrome climbs sharply above the age of 40—in both men and women—so much so that the syndrome is close to becoming the common feature for older age groups (FIGURE 1).
Studies find link to diabetes, cardiovascular disease
What evidence do we have that this syndrome is associated with an increased risk of diabetes, heart disease, and death?
In a study of slightly more than 1,000 males with 10 years of follow-up, Lakka et al4 found a 3.5-fold increased risk of cardiovascular disease mortality with metabolic syndrome. This risk is as high as or higher than the risk for cardiovascular disease in men with type 2 diabetes, which has been described in many other studies.
Risk rises with number of components
A more recent study explored the impact of the number of components of metabolic syndrome present.5 After controlling for age, family history of diabetes, alcohol intake, and cigarette smoking, investigators found a multivariate-adjusted relative risk of cardiovascular disease, compared with an absence of components, of 3.18, 3.48, 12.55, and 14.15 (P<.001 for the presence of and or more components respectively. corresponding relative risks type diabetes were>P<.001>
Another recent study used the coronary artery calcium score as a surrogate for cardiovascular disease.6 This measure is increasingly recognized as a marker of underlying atherosclerosis. In both men and women, the amount of calcium in the coronary arteries increased with the number of metabolic syndrome components.
Dyslipidemia is a critical component
Several studies have identified dyslipidemia as the key component of metabolic syndrome. That is not to say that other components are unimportant—only that lipid abnormalities appear to have the greatest impact.
In a trial from the Third National Health and Nutrition Examination Study (NHANES III),7 the large dataset that has been studied extensively for this disorder, low HDL cholesterol and high blood pressure in the presence of overt diabetes appeared to account for much of the excess risk associated with metabolic syndrome. In fact, blood pressure, HDL cholesterol, and diabetes—but not metabolic syndrome per se—were significant multivariate predictors of prevalent CHD.7
Twice the risk of myocardial infarction and stroke
Another recent study8 found twice the risk of myocardial infarction and stroke when metabolic syndrome was present.
Investigators used logistic regression to estimate the association of the syndrome as a whole and each of its 5 component conditions separately with a history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke).
Metabolic syndrome was significantly related in multivariate analysis to MI (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57).
Among the 5 component conditions of metabolic syndrome, the following were independently and significantly related to MI/stroke8:
- insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66),
- low HDL cholesterol (OR, 1.35; 95% CI, 1.05 to 1.74),
- hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and
- high triglycerides (OR, 1.66; 95% CI, 1.20 to 2.30).
With nutritionist counseling, glucose-impaired patients lost weight
Can lifestyle adjustments alone prevent type 2 diabetes to any great extent? Can anything be done to get overweight patients with impaired glucose to stick to a diet and exercise regimen?
Yes to both questions, according to researchers who conducted a randomized, controlled trial3 of lifestyle changes among 522 middle-aged, overweight men (n = 172) and women (n = 350) with impaired glucose tolerance and a mean body mass index of 31.
Chief intervention was nutritionist counseling
Nevertheless, getting the study participants to live healthier was a complex undertaking. The intervention group received individualized counseling to encourage them to:
- reduce their weight by 5% or more
- reduce fat consumption to less than 30%
- limit saturated fat intake to less than 10%
- eat 15 g or more of fiber per 1,000 kcal of intake
- exercise moderately for at least 30 minutes daily
- eat whole-grain products, fruits and vegetables, low-fat dairy products and meat, and vegetable oils rich in monounsaturated fatty acids.
Each person in the intervention group met with a nutritionist 7 times during the first year of the study and every 3 months thereafter. Dietary advice was based on 3-day diaries of food intake, completed quarterly.
Endurance exercise was recommended to increase aerobic capacity and improve cardiorespiratory function. In addition, progressive, individually tailored, circuit-type resistance training was offered to improve muscle strength. During the first year of the study, the rate of participation in these resistance training sessions ranged from 50% to 85%.
A very different picture for controls
In contrast to the individualized attention focused on the intervention group, controls received general oral and written information about diet and exercise at the beginning of the trial and at each annual visit, but no detailed counseling. They also completed a 3-day food diary at the beginning of the study and at each annual visit.
Risk of type 2 diabetes 58% lower
The percentage of patients in the intervention group who achieved a particular goal ranged from 25% (fiber consumption) to 86% (exercise). Net weight loss at the end of the second year was 3.5 ± 5.5 kg in the intervention group versus 0.8 ± 4.4 kg in the control group (P<.001 for both comparisons>
While this weight loss was not dramatic, the differences between groups was substantial. For example, individuals who lost at least 5% of their baseline weight had an odds ratio for diabetes of 0.3 (95 percent confidence interval, 0.1 to 0.7).
Over the duration of the trial, the cumulative incidence of type 2 diabetes was 58% lower in the intervention group than in the control group (P<.001>3 When women were singled out, the incidence of diabetes was 54% lower in the intervention group than among controls.
The failure to make any changes in lifestyle led to an incidence of diabetes very near the 35% estimate for this high-risk population.
Patients willingly stuck to diet, exercise
The dropout rate was low, and the researchers concluded that patients with impaired glucose tolerance are “willing and able to participate in a demanding intervention program if it is made available to them.”13
Unique lipid triad
High triglycerides, small LDL particles, and low HDL form the characteristic lipid profile of women with metabolic syndrome. For classification of the different levels of cholesterol, see TABLE 1.
High triglycerides heighten risk. High triglyceride levels carry an increased, independent risk of cardiovascular disease, particularly in women. As levels exceed 200 mg/dL, that risk rises sharply (FIGURE 2).9 Other studies, including a metaanalysis, have confirmed this finding.
Low HDL cholesterol is another independent risk factor for cardiovascular disease— one that is independent of standard risk markers such as LDL cholesterol. At high total cholesterol levels, the risk of cardiovascular disease increases, but that risk is even higher when HDL is low.10
Small LDL cholesterol particles. The characteristic LDL abnormality in patients with metabolic syndrome is not elevated levels, but a shift in size from larger to smaller LDL particles. In fact, the cardiovascular disease risk associated with small LDL particles is several times higher than the risk associated with the larger particles.
Smaller particles are more atherogenic than larger LDL particles despite their lower cholesterol content. The reasons:
They are cleared more slowly from plasma, taken up more readily by the artery wall, and more actively retained.
They are more rapidly oxidized, an important step in the atherogenic process.
At any level of LDL, there are more particles circulating.
Individuals tend to cluster into 2 groups based on LDL particle size: those with larger LDL particles, who usually have relatively lower triglyceride levels, and those with smaller LDL particles, who tend to have higher triglycerides. At triglyceride levels above 150 mg/dL—the cutoff for metabolic syndrome—individuals are more likely to have smaller LDL particles.
What is the risk associated with smaller particles? A study from 2001 by St. Pierre and colleagues11 showed that, at any level of triglycerides, LDL cholesterol, or apolipoprotein B (another LDL-related risk marker), the risk of coronary heart disease associated with small LDL particles is more than 3 times the risk associated with larger LDL particles.
TABLE 1
ATP III classification of LDL, total, and HDL cholesterol (mg/dL)
| LEVEL | STATUS |
|---|---|
| LDL cholesterol | |
| Optimal | |
| 100–129 | Near or above optimal |
| 130–159 | Borderline high |
| 160 –189 | High |
| ≥190 | Very high |
| Total cholesterol | |
| Desirable | |
| 200–239 | Borderline high |
| ≥240 | High |
| HDL cholesterol | |
| Low | |
| ≥60 | High |
| LDL = low-density lipoprotein | |
| HDL = high-density lipoprotein | |
| Source: NCEP.2 Reprinted with permission | |
C-reactive protein is an important marker
C-reactive protein is an important marker of the inflammation linked to heart disease. Elevated C-reactive protein also is associated with insulin resistance and adiposity. The trigger for the liver’s production of C-reactive protein is a cytokine released in large part by adipose tissue and endothelial cells.
Because a standardized, highly sensitive assay to measure plasma C-reactive protein is now available, there is a movement to include it in the definition of metabolic syndrome. As a recent study shows, the level of C-reactive protein rises with the number of components of metabolic syndrome.12 Levels tend to be higher in women than in men.
In addition, as Ridker et al13 and others have shown, as the levels of C-reactive protein rise from low (3 mg/L), so does the risk of cardiovascular disease.
Moreover, high C-reactive protein levels add to the risk associated with standard cholesterol-based risk factors. Thus, adding plasma C-reactive protein to standard lipid screening may help predict the risk of cardiovascular disease in women with high as well as low cholesterol levels.13 For example, if an individual has both elevated C-reactive protein and the metabolic syndrome, the relative risk of cardiovascular disease is more than twice the risk in women with high C-reactive protein alone.
First-line therapies are weight loss, exercise
According to ATP III2, the aims of managing metabolic syndrome are:
- to reduce causes of the syndrome, such as obesity and inactivity, and
- to treat lipid and nonlipid risk factors.
Weight loss enhances efforts to lower LDL cholesterol and reduces the impact of all risk factors for metabolic syndrome.2
Physical activity can reduce the risk of cardiovascular disease by improving cardiovascular fitness and coronary blood flow. Regular physical activity reduces very-lowdensity lipoprotein (VLDL) cholesterol levels, increases HDL cholesterol, and can lower LDL levels in some individuals. It also may help reduce blood pressure and insulin resistance.
ATP III recommends regular physical activity as a key component of managing high serum cholesterol.2 For more information on these interventions, see “Integrating evidence and experience”.
Why aggressive lipid lowering?
The current goal is reducing LDL cholesterol to less than 100 mg/dL when metabolic syndrome is present. Even lower levels, eg, less than 70 mg/dL, may be advisable when both cardiovascular disease and metabolic syndrome are present.14
A broader measure of atherogenic lipoproteins is total cholesterol minus HDL cholesterol. This measure incorporates some of the triglyceride-rich lipoproteins involved in atherosclerosis. The target is less than 130 mg/dL (TABLE 2).2 All people with borderline (150 to 199 mg/dL) or high (200 mg/dL or above) triglycerides should be managed to achieve this goal. Weight reduction and physical activity are critical, even with drug therapy.
TABLE 2
Comparison of LDL and non-HDL cholesterol goals for 3 risk categories
| RISK CATEGORY | LDL GOAL (MG/DL) | NON-HDL GOAL (MG/DL) |
|---|---|---|
| Coronary heart disease or risk equivalent (10-year risk for coronary heart disease >20%) | ||
| 2 or more risk factors and 10-year risk 20% | ||
| 0–1 risk factor | ||
| LDL = low-density lipoprotein | ||
| HDL = high-density lipoprotein | ||
| Source: NCEP.2 Reprinted with permission | ||
When to use drug therapy
Pharmacologic intervention to lower non-HDL cholesterol may involve use of an LDL-lowering drug or the addition of nicotinic acid or fibrate to reduce VLDL.
When triglyceride levels are extremely high (500 mg/dL or higher), the primary goal of therapy is preventing acute pancreatitis. This may require a combination of low-fat diet, weight loss, regular physical activity, and a triglyceride-lowering drug.2 Once triglyceride levels decline to less than 500 mg/dL, the emphasis can return to reducing cardiovascular risk.
When LDL cholesterol is very high. LDL cholesterol levels of 190 mg/dL or higher, usually signify genetic hypercholesterolemia.2 Early detection—preferably, in young adults—is crucial to prevent coronary heart disease, and a combination of drugs usually is necessary to reduce LDL cholesterol levels. Otherwise, aim for the goals in TABLE 2.
Benefits of statins. In a post hoc analysis of data from the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol and coronary heart disease, those with the triad of elevated LDL cholesterol, low HDL cholesterol, and elevated triglycerides were more likely than patients with isolated high LDL cholesterol to have other characteristics of the metabolic syndrome. They also had a greater risk of coronary heart disease on placebo and received greater benefit with simvastatin therapy.15
Fibrates and HDL cholesterol. In a subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, investigators explored the efficacy of gemfibrozil in men with coronary heart disease, HDL cholesterol levels of 40 mg/dL or below, and LDL cholesterol of 140 mg/dL or less.16
Participants were given 1,200 mg of gemfibrozil daily and followed for an average of 5.1 years. The drug was most effective in those with diabetes, reducing death from coronary heart disease by 41% (hazard ratio, 0.59; 95% confidence interval, 0.39–0.91; P<.02>
Among men without diabetes, gemfibrozil was most effective for those in the highest quartile for fasting plasma insulin (risk reduction 35%; P<.04>
Among those who had coronary heart disease and low HDL cholesterol, the drug reduced major cardiovascular events.
Nicotinic acid improves each of the common lipid abnormalities found in metabolic syndrome.17 Early concern that it can precipitate or worsen diabetes has largely been disproved, although some data suggest that it can slightly aggravate insulin resistance and elevate blood glucose.
When it comes to cognitive function, is metabolic syndrome a “brain drain”?
A recent prospective observational study14 found a link between metabolic syndrome and cognitive impairment in the elderly, particularly when inflammation also was present.
Hypertension, diabetes, and other cardiovascular and metabolic risk factors are thought to play a role in the development of Alzheimer’s disease and vascular dementia.
Researchers followed 2,632 elderly men and women over 5 years (mean age: 74), documenting metabolic syndrome in 1,016. Those with metabolic syndrome were more likely to have cognitive impairment (26% versus 21%; multivariate-adjusted relative risk [RR], 1.20; 95% confidence interval [CI], 1.02–1.41) than were those without the syndrome.
Investigators also documented high inflammation in the study population, defining it as higher-than-median serum levels of both interleukin 6 (≥2 pg/mL) and C-reactive protein (≥2 mg/L). They then assessed its relationship to cognitive decline.
Those with both metabolic syndrome and high inflammation had an increased likelihood of cognitive impairment, compared with those without metabolic syndrome (multivariate-adjusted RR, 1.66; 95% CI, 1.19–2.32).
Those with metabolic syndrome and low inflammation had a low likelihood of impairment (multivariate-adjusted RR, 1.08; 95% CI, 0.89–1.30).
These findings held true even after adjusting for demographics, comorbidities, and health habits. It remains to be seen whether attempts to prevent metabolic syndrome or lower inflammation also limit cognitive impairment.
1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Examination Study. JAMA. 2002;287:356-359.
2. Expert Panel on Detection. Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
4. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.
5. Nakanishi N, Takatorige T, Fukuda H, et al. Components of the metabolic syndrome as predictors of cardiovascular disease and type 2 diabetes in middle-aged Japanese men. Diabetes Res Clin Pract. 2004;64:59-70.
6. Reilly MP, Wolfe ML, Rhodes T, et al. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation. 2004;110:803-809.
7. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.
8. Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109:42-46.
9. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H.
10. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256:2835-2838.
11. St. Pierre, et al. Circulation. 2001;104:2295.-
12. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380-385.
13. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813-1818.
14. Yaffe K, Kamaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237-2242.
15. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.
16. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs highdensity lipoprotein intervention trial (VA-HIT). Arch Intern Med. 2002;162:2597-2604.
17. Meyers CD, Kashyap ML. Management of the metabolic syndrome—nicotinic acid. Endocrinol Metab Clin North Am. 2004;33:557-575.
1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults. Findings from the Third National Health and Nutrition Examination Study. JAMA. 2002;287:356-359.
2. Expert Panel on Detection. Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
4. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.
5. Nakanishi N, Takatorige T, Fukuda H, et al. Components of the metabolic syndrome as predictors of cardiovascular disease and type 2 diabetes in middle-aged Japanese men. Diabetes Res Clin Pract. 2004;64:59-70.
6. Reilly MP, Wolfe ML, Rhodes T, et al. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation. 2004;110:803-809.
7. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.
8. Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109:42-46.
9. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70(19):3H-9H.
10. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256:2835-2838.
11. St. Pierre, et al. Circulation. 2001;104:2295.-
12. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380-385.
13. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813-1818.
14. Yaffe K, Kamaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237-2242.
15. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.
16. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs highdensity lipoprotein intervention trial (VA-HIT). Arch Intern Med. 2002;162:2597-2604.
17. Meyers CD, Kashyap ML. Management of the metabolic syndrome—nicotinic acid. Endocrinol Metab Clin North Am. 2004;33:557-575.
A Tobacco Cessation Program for Veterans
Using Transesophageal Echocardiography to Guide Early Cardioversion
Promising therapies: TOT, duloxetine, botulinum A
Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.
20% cancel surgery after duloxetine therapy
Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.
Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.
A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.
The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.
Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.
Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.
Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.
Cure rate low, but so is risk
Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.
In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.
While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.
Botulinum A toxin for refractory detrusor overactivity
Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.
Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.
Previously, such women might have been treated with electrical stimulation.
This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.
Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.
In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).
Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).
Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.
Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.
Stress incontinence surgery: What’s in, what’s out
Is TVT out?
Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.
Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.
The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.
In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).
Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.
Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.
TOT (but not silicone) is in
Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.
This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!
Laparoscopic Burch is out
Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.
What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.
Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.
One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.
Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.
Watch for these 2 reports
In other incontinence news, look for results from 2 important trials in 2006:
- Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
- Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
A reminder: Inform the patient
Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.
Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.
20% cancel surgery after duloxetine therapy
Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.
Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.
A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.
The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.
Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.
Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.
Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.
Cure rate low, but so is risk
Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.
In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.
While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.
Botulinum A toxin for refractory detrusor overactivity
Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.
Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.
Previously, such women might have been treated with electrical stimulation.
This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.
Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.
In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).
Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).
Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.
Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.
Stress incontinence surgery: What’s in, what’s out
Is TVT out?
Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.
Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.
The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.
In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).
Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.
Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.
TOT (but not silicone) is in
Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.
This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!
Laparoscopic Burch is out
Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.
What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.
Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.
One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.
Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.
Watch for these 2 reports
In other incontinence news, look for results from 2 important trials in 2006:
- Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
- Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
A reminder: Inform the patient
Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.
Ob/Gyns are being called on more than ever to initiate treatment for urinary incontinence, and new treatment options are enabling us to play a more active role than ever before in treating one of the most common and distressing of chronic diseases in women. Urinary incontinence affects women after menopause, primarily. Prevalence increases (though not in a linear fashion)—from 20% to 30% in reproductive-aged women, to 30% to 40% in postmenopausal women. Approximately 16 million Americans are affected, and the number of women affected is more than double that of men.
20% cancel surgery after duloxetine therapy
Efforts to treat stress incontinence with drugs have not succeeded well in the past, but the development of duloxetine may change that.
Duloxetine (Cymbalta; Eli Lilly, Indianapolis, Ind) is a balanced serotonin-norepinephrine reuptake inhibitor that may act by stimulating pudendal nerve output and improving urethral closure. The FDA approved duloxetine for treatment of major depression for adults in August 2004, and for management of diabetic peripheral neuropathic pain in September 2004. However, duloxetine is not yet FDA-approved for the treatment of stress incontinence.
A randomized, placebo-controlled, double-blinded study involving 14 centers in Australia, Canada, the Netherlands, and the United Kingdom enrolled women aged 18 to 75 years, all of whom had severe stress incontinence, and had already scheduled surgery. All patients had at least 14 episodes of stress incontinence per week. The dose of duloxetine started at 40 mg twice daily for 4 weeks, then increased to 60 mg twice daily for another 4 weeks.
The study randomized 109 women and included 98 in the intention-to-treat analyses, 46 of whom took duloxetine, and 52, placebo.
Response was defined as at least a 50% reduction in incontinence episode frequency. Of the women taking duloxetine, 63% were responders, compared with 13.5% of the placebo group.
Using the Patient Global Impression of Improvement (PGI-I), one third of women taking duloxetine described themselves as “very much better” or “much better,” compared with 8% of women taking placebo.
Ten of 49 women (20%) indicated they were not interested in surgery while taking duloxetine, compared with 0 of 45 women taking placebo. Drug discontinuation occurred more frequently in the duloxetine group: 18 of 55 (33%), compared with 3 of 54 (6%) in the placebo group.
Cure rate low, but so is risk
Even if the “cure” rate is relatively low, duloxetine offers a low-risk form of treatment for women who might otherwise be considered surgical candidates.
In addition, pharmacological treatment may be indicated for women whose incontinence is not severe enough to warrant surgery.
While there are no studies that report long-term results of duloxetine use, it seems appropriate that duloxetine be included in the discussion of nonsurgical options, along with pelvic muscle exercises and behavioral treatment, before surgery is considered.
Botulinum A toxin for refractory detrusor overactivity
Cystoscopic detrusor injection of botulinum toxin A appears to be a promising alternative to more invasive treatments for refractory detrusor overactivity.
Urinary incontinence due to detrusor overactivity can be especially difficult to treat when first-line treatment with anticholinergic drugs is unsuccessful. Although newer slow-release or long-acting formulations are tolerated better than the original formulations, many patients still have bothersome symptoms or intolerable side effects.
Previously, such women might have been treated with electrical stimulation.
This less invasive treatment might be an effective option, although further study is needed to identify patients most likely to benefit.
Effectiveness has been observed in patients with detrusor overactivity due to spinal cord injury and, in the study cited above, in patients with neurogenic, idiopathic, and postobstructive detrusor over-activity. Botulinum toxin A is not FDA-approved for incontinence indications.
In the Kuo study, 30 patients (12 women and 18 men) with detrusor overactivity refractory to anticholinergic agents were treated with cystoscopic detrusor injection of 200 units botulinum toxin A at 40 sites in the posterior and lateral bladder (sparing the anterior bladder). Eight patients (27%) regained urinary continence; 14 (46%) had improvement in frequency, urgency, and incontinence; and treatment failed in 8 (27%).
Excellent results were most likely in patients with previous bladder outlet obstruction, and least likely in patients with neurogenic detrusor overactivity. Men were more often successfully treated (83%) than women (58%). Maximal effect was noted at 10 to 14 days after treatment, and the effect lasted 3 to 9 months (average, 5.3 months).
Side effects were not serious: urinary tract infection in 3 patients and transient urinary retention in 4. Six patients with detrusor overactivity and impaired contractility were treated with intermittent self-catheterization for 1 month, after treatment resulted in increased postvoid residual urine volumes.
Patients with impaired bladder emptying before treatment may be at higher risk of posttreatment retention, although even when retention occurs, it seems to be transient and responds well to time-limited management with intermittent self-catheterization.
Stress incontinence surgery: What’s in, what’s out
Is TVT out?
Costa P, Grise P, Droupy S, et al. Surgical treatment of female stress urinary incontinence with a transobturator-tape (TOT) Uratape: Short-term results of a prospective multicentric study. Eur Urol. 2004;46:102–107.
Faster than you can say “tension-free vaginal tape,” an even newer procedure is coming to the fore: TOT, the transobturator tape.
The TVT operation revolutionized stress incontinence surgery, with placement at the midurethra instead of traditional placement at the bladder neck. Although case series and the first randomized trials showed good results with TVT, concern about retropubic complications fueled development of alternate placement through the obturator foramen. This alternative is intended to avoid complications attributable to penetration of the peritoneal cavity or retropubic space with TVT.
In a study conducted by Costa et al, 183 women with stress or mixed incontinence associated with urethral hypermobility underwent the TOT procedure, which involved midurethral placement of a polypropylene tape with a silicone-coated central part, using a transobturator percutaneous approach. With follow-up at more than 6 months on 130 of the 183 study subjects, 83% were reported as “cured” (absence of subjective complaint of urine leakage and absence of leakage on cough stress testing) and 5.4% as “improved” (decrease of stress incontinence, not further specified).
Obviously, we need more information and, ideally, comparative information to determine how this new technique fits in with other surgical options for stress incontinence. So far, 2 trials comparing TVT and TOT were reported in abstract at the 2004 meeting of the International Continence Society.
Of 17 failures, tape removal was necessary in 5, due to vaginal extrusion in 3 and urethral erosion in 2. Because of this high rate of extrusion, the silicone portion of the tape has been removed.
TOT (but not silicone) is in
Comiter CV, Colegrove PM. High rate of vaginal extrusion of silicone-coated polyester sling. Urology. 2004;63:1066–1070.
This case series reported 10 patients treated with the silicone-coated polyester sling for stress or mixed urinary incontinence. Two patients (20%) developed vaginal extrusion requiring tape removal, at 6 and at 10 months after initial placement. Although the sling was otherwise effective in treating stress incontinence, this high rate of extrusion obviously precludes further use. No silicone on slings!
Laparoscopic Burch is out
Ankardal M, Ekerydh A, Crafoord K, et al. A randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Br J Obstet Gynaecol. 2004;111:974–981.
What about laparoscopy, the grandfather of minimally invasive surgery? In this large, adequately powered, randomized trial of open Burch and laparoscopic colposuspension, the open technique was performed with permanent suture, 2 stitches on each side; the laparoscopic technique used polypropylene mesh and titanium staples. Of 120 subjects randomly assigned to each group, 98 underwent open and 109 underwent laparoscopic colposuspension.
Unfortunately, twice as many subjects (22) assigned to open Burch were excluded after randomization, compared with the laparoscopic group (11). Nonetheless, the results 1 year after surgery unequivocally favored open versus laparoscopic colposuspension: objective cure by pad test in 92% versus 74%, and subjectively dry in 89% versus 62%, respectively.
One wonders why any more trials of laparoscopic colposuspension should be performed at all, although the authors call for future randomized studies comparing different laparoscopic techniques such as suture versus staples and mesh. If the goal is to provide effective, “minimally invasive” surgery for incontinence, with traditional slings updated to include TVT and now TOT, it seems we already have reasonably good alternatives—with the caveat, “pending further studies,” especially for long-term results of the new techniques.
Clinicians who prefer slings have always wondered why laparoscopy—with 3 or 4 abdominal ports, pneumoperitoneum, and general anesthesia—was seen as minimally invasive. Not that laparoscopic continence procedures should never be performed, but it seems likely that they will occupy a narrow niche in the range of surgeries for stress incontinence in women.
Watch for these 2 reports
In other incontinence news, look for results from 2 important trials in 2006:
- Burch versus sling in 650 women with stress incontinence; performed by the Urinary Incontinence Treatment Network (an NIH-funded network of 9 clinical sites).
- Burch versus no Burch in 480 women without stress incontinence symptoms with advanced prolapse undergoing abdominal sacral colpopexy; performed by the Pelvic Floor Disorders Network (an NIH-funded network of 7 clinical sites).
A reminder: Inform the patient
Dr. Weber serves as an NIH consultant, and reports no other financial relationships in any other capacity.
Pap test every year? Not for every woman
Putting new guidelines into practice is easier said than done
Steven Goldstein, MD
New York University Medical Center
Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.
And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.3
Original rationale: “Pap smear prompt”
These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.
In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.4
Frequent screening would detect exceedingly few additional cancers, at an exceedingly high cost
We can confidently counsel patients
A previously well-screened woman over age 30 who has no history of dysplasia has an exceedingly small risk of cervical cancer, whether her next Pap test is 1, 2, or 3 years after her last.
How many cancers will we miss?
Miller MG, Sung HY, Sawaya GF, Kearney KA, Kinney W, Hiatt RA. Screening interval and risk of invasive squamous cell cervical cancer. Obstet Gynecol. 2003;101:29-37.
This matched case-control study assessed the odds of being diagnosed with squamous cell cervical cancer when a Pap test is performed 2 or 3 years versus 1 year after a normal Pap. Data from the Kaiser Permanente Medical Care Program in Northern California was used to identify 482 women who were diagnosed with invasive squamous cell cervical cancer between 1983 and 1995, and to compare each woman with 2 control individuals matched for age, race/ethnicity, and length of program membership. An intact cervix and no prior cervical, uterine, or vaginal cancer were required. A woman who had a Pap test within 18 months of her last negative test was half as likely to have invasive cancer as a woman who waited 3 years (31 to 42 months).
The odds ratios for invasive cancer diagnosed by screening at 1, 2, or 3 years were 1.00, 1.72, and 2.06, respectively. The differences between intervals of 2 or 3 years versus 1 year were significant. The odds ratios increased to 2.15 and 3.60, respectively, in women with at least 2 consecutive negative Pap tests prior to diagnosis.
In all analyses, the odds ratios continued to increase as screening intervals were prolonged beyond 3 years.
Increased relative risk and very small absolute risk. The new ACOG and ACS guidelines recommend extending the screening interval only for women over 30 who have been well screened over the previous decade. This study does not break down the relative risks by age, nor does the sample size allow assessment of the risks for women with more than 2 consecutive negative Paps.
The authors note that the age-adjusted incidence of invasive cervical cancer among all Northern California Kaiser Permanente members is only 6.2 per 100,000 women. In this well-screened population, even doubling the relative risk leaves a very small absolute risk of cervical cancer.
How many fruitless interventions?
Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
If screening were done annually rather than every 3 years, how many additional tests would be needed to diagnose each additional cancer expected to be found? To find out, Sawaya et al applied data from the National Breast and Cervical Cancer Early Detection Program to a Markov model. They studied 32,230 women with 3 successive negative Pap tests, each no more than 36 months apart.
They predicted that, in a theoretical cohort of 100,000 women who had at least 3 consecutive negative Pap tests, screening at 1-year rather than 3-year intervals would uncover 3 additional cancers in women aged 30 to 44, a single additional cancer in women aged 45 to 59, and no additional cancers for women 60 to 64 years of age.
They calculated that, for this theoretical cohort of 100,000 women:
- To find all 3 additional cancers in the 30- to 44-year-old group would require 69,665 Pap tests and 3,861 colposcopies.
- To find the only additional cancer in the 45- to 59-year-old group would require 209,324 Pap tests and 11,502 colposcopies.
As with all modeling studies, Sawaya’s analysis is limited by the assumptions introduced into the model.
Among them:
- perfect compliance on the part of this cohort of hypothetical patients,
- use of conventional Pap tests only, and
- uniform sensitivity and specificity.
Why change? How will patients react?
Cumulative findings suggest an age- and risk-based approach
Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.
The main questions
In this article, I’ll review some of the data on these concerns:
- Why wait 3 years after first intercourse for the first Pap test?
- Why is 21 the ‘default’ age for first Pap test?
- What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
- Do most women without a cervix require screening?
- What is the role of HPV DNA testing?
- How should we deal with abnormal results?
- How should we counsel the patient?
- What’s the harm in continuing Pap tests in all women?
- Will women return for annual exams as we advise, if we change their Pap test routine?
ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?
Care is not compromised
Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.
Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.
We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.5,6
We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.7
HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.9
The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.10 Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.
Don’t neglect counseling, STD testing, birth control
Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.
October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion11 to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.
AGES 21 TO 30Why is age 21 the “default” for first Pap?
Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,12 cytology screening should start at age 21, irrespective of sexual history. Saslow et al1 writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.
Aggressive screening until age 30
Women should be screened every year until age 30 if conventional Pap smears are used.1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.
Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.
Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.
Does type of Pap test determine screening interval?
Every 2 years is sufficient if the liquid Pap test is used: ACS.1 This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.
Annual tests until age 30, irrespective of Pap technology: ACOG.2 That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.
AGES 30 TO 65Why extend the interval between Pap tests?
High risk calls for yearly screens
Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.
Risk factors include:
- history of cervical cancer,
- immunocompromise including HIV,
- in utero exposure to diethylstilbestrol (DES), and
- women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
Longer interval if risk is low
Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.13
Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:
- These women have the protection offered by frequent Pap tests during the previous decade.
- By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.14
Studies of screening effects
National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al13 studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.
International Agency for Research in Cancer15 data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.
National Breast and Cervical Cancer Early Detection Program16 data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.
Do postmenopausal women need screening?
Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.17 Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.
An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.3
The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.1
ACOG does not set a specific upper age for cytology screening.2 While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.
ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.
Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,18 using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.
Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.
Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.
Screen for cervical cancer if there is no cervix?
Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.19
For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.
In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.9 Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.
What is the role of HPV testing?
Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.1,2
Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.
High negative predictive value after age 30
On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.12 Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al21 determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.
Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.
It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.
ABNORMAL RESULTSConsensus guidelines for combined testing
Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.22
ASC-US and positive HPV
Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.23 Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.
When cytology results are more severe than ASC-US
If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.
Negative cytology and positive for high-risk HPV
This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.21 While most HPV infections are transient, the risk of dysplasia increases when they persist.24 A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.
The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.
If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.
Counseling HPV-positive patients
Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.
Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.
Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.
Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.
Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.
Let her know her partner probably carries the same HPV type, or has cleared it in the past.
Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.
Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.
What’s the harm in yearly testing?
Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?
These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.
Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.13
Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.
But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.
The authors report no relevant financial relationships.
1. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guidelines for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. November-December 2002;52:342-362.
2. American College of Obstetricians and Gynecologists. Practice bulletin No. 45: cervical cytology screening. Obstet Gynecol. 2003;102:417-427.
3. US Preventative Services Task Force. Screening for cervical cancer. Rockville, Md: Agency for Healthcare Research and Quality; 2003. Available at: http://www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanwh.pdf. Accessed November 1, 2004.
4. American College of Obstetricians and Gynecologists. Technical bulletin No. 29: the frequency with which a cervical-vaginal cytology examination should be performed in gynecologic practice. Washington, DC: ACOG; February 1975.
5. Muñoz N, Bosch X, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Eng J Med. 2003;348:518-527.
6. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19.
7. Ho GY, Bierman R, Beardsley L, et al. The natural history of cervical papillomavirus infection in young women. N Engl J Med. 1998;338:423-428.
8. Moscicki AB, Shiboski S., Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277-284.
9. Moscicki AB. Cervical cytology screening in teens. Curr Womens Health Rep. 2003;3:433-437.
10. Reis LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975-2001. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2001/. Accessed November 8, 2004.
11. American College of Obstetricians and Gynecologists. Committee opinion No. 300: cervical cancer screening in adolescents. Obstet Gynecol. 2004;104:885-889.
12. Kulasingam SL, Hughes JP, Kiviat NB, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288:1749-1757.
13. Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
14. Moscicki AB, Burt VG, Kanowitz S, et al. The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. Cancer. 1999;85:1139-1144.
15. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed). 1986;293:659-664.
16. Sawaya GF, Kerlikowske K, Lee NC, et al. Frequency of cervical smear abnormalities within 3 years of normal cytology. Obstet Gyncol. 2000;96:219-223.
17. NIH Consensus statement: cervical cancer. National Institutes of Health. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, 1996;14:1-38.
18. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/Progestin Replacement Study (HERS). Ann Intern Med. 2000;133:942-950.
19. Sirovich BE, Welch HG. Cervical cancer screening among women without a cervix. JAMA. 2004;291:2990-2993.
20. Sellors JW, Karwalajtys TL, Kaczorowski JA, et al. Prevalence of infection with carcinogenic human papillomavirus among older women. CMAJ. 2002;167:871-873.
21. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46-52.
22. Wright TC, Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-309.
23. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383-1392.
24. Schlect NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA. 2001;286:3106-3114.
Putting new guidelines into practice is easier said than done
Steven Goldstein, MD
New York University Medical Center
Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.
And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.3
Original rationale: “Pap smear prompt”
These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.
In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.4
Frequent screening would detect exceedingly few additional cancers, at an exceedingly high cost
We can confidently counsel patients
A previously well-screened woman over age 30 who has no history of dysplasia has an exceedingly small risk of cervical cancer, whether her next Pap test is 1, 2, or 3 years after her last.
How many cancers will we miss?
Miller MG, Sung HY, Sawaya GF, Kearney KA, Kinney W, Hiatt RA. Screening interval and risk of invasive squamous cell cervical cancer. Obstet Gynecol. 2003;101:29-37.
This matched case-control study assessed the odds of being diagnosed with squamous cell cervical cancer when a Pap test is performed 2 or 3 years versus 1 year after a normal Pap. Data from the Kaiser Permanente Medical Care Program in Northern California was used to identify 482 women who were diagnosed with invasive squamous cell cervical cancer between 1983 and 1995, and to compare each woman with 2 control individuals matched for age, race/ethnicity, and length of program membership. An intact cervix and no prior cervical, uterine, or vaginal cancer were required. A woman who had a Pap test within 18 months of her last negative test was half as likely to have invasive cancer as a woman who waited 3 years (31 to 42 months).
The odds ratios for invasive cancer diagnosed by screening at 1, 2, or 3 years were 1.00, 1.72, and 2.06, respectively. The differences between intervals of 2 or 3 years versus 1 year were significant. The odds ratios increased to 2.15 and 3.60, respectively, in women with at least 2 consecutive negative Pap tests prior to diagnosis.
In all analyses, the odds ratios continued to increase as screening intervals were prolonged beyond 3 years.
Increased relative risk and very small absolute risk. The new ACOG and ACS guidelines recommend extending the screening interval only for women over 30 who have been well screened over the previous decade. This study does not break down the relative risks by age, nor does the sample size allow assessment of the risks for women with more than 2 consecutive negative Paps.
The authors note that the age-adjusted incidence of invasive cervical cancer among all Northern California Kaiser Permanente members is only 6.2 per 100,000 women. In this well-screened population, even doubling the relative risk leaves a very small absolute risk of cervical cancer.
How many fruitless interventions?
Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
If screening were done annually rather than every 3 years, how many additional tests would be needed to diagnose each additional cancer expected to be found? To find out, Sawaya et al applied data from the National Breast and Cervical Cancer Early Detection Program to a Markov model. They studied 32,230 women with 3 successive negative Pap tests, each no more than 36 months apart.
They predicted that, in a theoretical cohort of 100,000 women who had at least 3 consecutive negative Pap tests, screening at 1-year rather than 3-year intervals would uncover 3 additional cancers in women aged 30 to 44, a single additional cancer in women aged 45 to 59, and no additional cancers for women 60 to 64 years of age.
They calculated that, for this theoretical cohort of 100,000 women:
- To find all 3 additional cancers in the 30- to 44-year-old group would require 69,665 Pap tests and 3,861 colposcopies.
- To find the only additional cancer in the 45- to 59-year-old group would require 209,324 Pap tests and 11,502 colposcopies.
As with all modeling studies, Sawaya’s analysis is limited by the assumptions introduced into the model.
Among them:
- perfect compliance on the part of this cohort of hypothetical patients,
- use of conventional Pap tests only, and
- uniform sensitivity and specificity.
Why change? How will patients react?
Cumulative findings suggest an age- and risk-based approach
Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.
The main questions
In this article, I’ll review some of the data on these concerns:
- Why wait 3 years after first intercourse for the first Pap test?
- Why is 21 the ‘default’ age for first Pap test?
- What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
- Do most women without a cervix require screening?
- What is the role of HPV DNA testing?
- How should we deal with abnormal results?
- How should we counsel the patient?
- What’s the harm in continuing Pap tests in all women?
- Will women return for annual exams as we advise, if we change their Pap test routine?
ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?
Care is not compromised
Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.
Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.
We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.5,6
We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.7
HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.9
The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.10 Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.
Don’t neglect counseling, STD testing, birth control
Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.
October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion11 to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.
AGES 21 TO 30Why is age 21 the “default” for first Pap?
Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,12 cytology screening should start at age 21, irrespective of sexual history. Saslow et al1 writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.
Aggressive screening until age 30
Women should be screened every year until age 30 if conventional Pap smears are used.1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.
Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.
Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.
Does type of Pap test determine screening interval?
Every 2 years is sufficient if the liquid Pap test is used: ACS.1 This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.
Annual tests until age 30, irrespective of Pap technology: ACOG.2 That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.
AGES 30 TO 65Why extend the interval between Pap tests?
High risk calls for yearly screens
Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.
Risk factors include:
- history of cervical cancer,
- immunocompromise including HIV,
- in utero exposure to diethylstilbestrol (DES), and
- women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
Longer interval if risk is low
Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.13
Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:
- These women have the protection offered by frequent Pap tests during the previous decade.
- By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.14
Studies of screening effects
National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al13 studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.
International Agency for Research in Cancer15 data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.
National Breast and Cervical Cancer Early Detection Program16 data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.
Do postmenopausal women need screening?
Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.17 Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.
An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.3
The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.1
ACOG does not set a specific upper age for cytology screening.2 While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.
ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.
Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,18 using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.
Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.
Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.
Screen for cervical cancer if there is no cervix?
Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.19
For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.
In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.9 Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.
What is the role of HPV testing?
Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.1,2
Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.
High negative predictive value after age 30
On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.12 Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al21 determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.
Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.
It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.
ABNORMAL RESULTSConsensus guidelines for combined testing
Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.22
ASC-US and positive HPV
Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.23 Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.
When cytology results are more severe than ASC-US
If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.
Negative cytology and positive for high-risk HPV
This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.21 While most HPV infections are transient, the risk of dysplasia increases when they persist.24 A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.
The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.
If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.
Counseling HPV-positive patients
Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.
Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.
Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.
Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.
Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.
Let her know her partner probably carries the same HPV type, or has cleared it in the past.
Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.
Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.
What’s the harm in yearly testing?
Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?
These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.
Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.13
Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.
But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.
The authors report no relevant financial relationships.
Putting new guidelines into practice is easier said than done
Steven Goldstein, MD
New York University Medical Center
Is the Pap test still necessary for every woman, every year? No, according to the latest guidelines, but old habits die hard, even for physicians.
And there is little doubt that yearly screening, though not scientifically based, has contributed much to the reduction of cervical cancer incidence and mortality in American women. Our patients and we as providers have long considered a Pap test the cornerstone of the annual gynecologic exam, as we’ve been urged to do for decades by our leading academic institutions. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society (ACS) revised their guidelines last year, and no longer support yearly screening for every woman, every year.1,2 The US Preventive Services Task Force (USPSTF) revised its guidelines in accord, with the exception that it found the evidence insufficient to support screening low-risk women more often than every 3 years, at any age.3
Original rationale: “Pap smear prompt”
These organizations, as well as the National Cancer Institutes (NCI), had supported annual Pap testing since the mid-1950s—long before any data suggested whether one screening interval might be better than another.
In fact, part of the original rationale for annual screening was that it would serve as a vehicle to bring women in for their annual gynecologic exam.4
Frequent screening would detect exceedingly few additional cancers, at an exceedingly high cost
We can confidently counsel patients
A previously well-screened woman over age 30 who has no history of dysplasia has an exceedingly small risk of cervical cancer, whether her next Pap test is 1, 2, or 3 years after her last.
How many cancers will we miss?
Miller MG, Sung HY, Sawaya GF, Kearney KA, Kinney W, Hiatt RA. Screening interval and risk of invasive squamous cell cervical cancer. Obstet Gynecol. 2003;101:29-37.
This matched case-control study assessed the odds of being diagnosed with squamous cell cervical cancer when a Pap test is performed 2 or 3 years versus 1 year after a normal Pap. Data from the Kaiser Permanente Medical Care Program in Northern California was used to identify 482 women who were diagnosed with invasive squamous cell cervical cancer between 1983 and 1995, and to compare each woman with 2 control individuals matched for age, race/ethnicity, and length of program membership. An intact cervix and no prior cervical, uterine, or vaginal cancer were required. A woman who had a Pap test within 18 months of her last negative test was half as likely to have invasive cancer as a woman who waited 3 years (31 to 42 months).
The odds ratios for invasive cancer diagnosed by screening at 1, 2, or 3 years were 1.00, 1.72, and 2.06, respectively. The differences between intervals of 2 or 3 years versus 1 year were significant. The odds ratios increased to 2.15 and 3.60, respectively, in women with at least 2 consecutive negative Pap tests prior to diagnosis.
In all analyses, the odds ratios continued to increase as screening intervals were prolonged beyond 3 years.
Increased relative risk and very small absolute risk. The new ACOG and ACS guidelines recommend extending the screening interval only for women over 30 who have been well screened over the previous decade. This study does not break down the relative risks by age, nor does the sample size allow assessment of the risks for women with more than 2 consecutive negative Paps.
The authors note that the age-adjusted incidence of invasive cervical cancer among all Northern California Kaiser Permanente members is only 6.2 per 100,000 women. In this well-screened population, even doubling the relative risk leaves a very small absolute risk of cervical cancer.
How many fruitless interventions?
Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
If screening were done annually rather than every 3 years, how many additional tests would be needed to diagnose each additional cancer expected to be found? To find out, Sawaya et al applied data from the National Breast and Cervical Cancer Early Detection Program to a Markov model. They studied 32,230 women with 3 successive negative Pap tests, each no more than 36 months apart.
They predicted that, in a theoretical cohort of 100,000 women who had at least 3 consecutive negative Pap tests, screening at 1-year rather than 3-year intervals would uncover 3 additional cancers in women aged 30 to 44, a single additional cancer in women aged 45 to 59, and no additional cancers for women 60 to 64 years of age.
They calculated that, for this theoretical cohort of 100,000 women:
- To find all 3 additional cancers in the 30- to 44-year-old group would require 69,665 Pap tests and 3,861 colposcopies.
- To find the only additional cancer in the 45- to 59-year-old group would require 209,324 Pap tests and 11,502 colposcopies.
As with all modeling studies, Sawaya’s analysis is limited by the assumptions introduced into the model.
Among them:
- perfect compliance on the part of this cohort of hypothetical patients,
- use of conventional Pap tests only, and
- uniform sensitivity and specificity.
Why change? How will patients react?
Cumulative findings suggest an age- and risk-based approach
Research over the past few decades has revealed much about the pathogenesis of cervical cancer which supports an age- and risk-based approach to screening for cervical cancer—when to start, when to stop, and how often to perform cervical cytology.
The main questions
In this article, I’ll review some of the data on these concerns:
- Why wait 3 years after first intercourse for the first Pap test?
- Why is 21 the ‘default’ age for first Pap test?
- What are the risks and costs of screening every 2 to 3 years in well-screened women over age 30? Over age 65?
- Do most women without a cervix require screening?
- What is the role of HPV DNA testing?
- How should we deal with abnormal results?
- How should we counsel the patient?
- What’s the harm in continuing Pap tests in all women?
- Will women return for annual exams as we advise, if we change their Pap test routine?
ADOLESCENCEWhy wait 3 years after onset of intercourse for first Pap test?
Care is not compromised
Delaying screening until at least 3 years after coitarche does not compromise the diagnosis of high-grade lesions, yet does allow discovery and eradication long before they become malignant. On the other hand, screening young women sooner than 3 years after first sexual intercourse risks diagnosing numerous self-limited HPV infections and transient low-grade dysplastic lesions, which have very low premalignant potential.
Persistent high-risk HPV must precede cancer. Cervical cancer develops only after persistent HPV infection, many years from the initial HPV exposure.
We now know that at least 15 to 18 types of human papillomavirus (HPV) can cause cervical cancer, and that infection with a high-risk type of HPV is the necessary antecedent—but not by itself a sufficient antecedent—for high-grade cervical dysplasia and cervical cancer.5,6
We also know that HPV is most often acquired through sexual intercourse and that it is very efficiently acquired by young women.7,8 For example, a study of young college women who were initially HPV negative acquired HPV at a rate of 14% per year.7
HPV infections in young women are usually transient, however. Up to 90% of young women who test positive for HPV DNA will revert to negative within 2 years.9
The problems of screening too early. Squamous cancer of the cervix is exceedingly rare in women under age 21.10 Diagnosis of self-limited HPV infections and transient low-grade dysplastic lesions would likely result in repeat Pap tests and colposcopies. In addition to being costly and anxiety-provoking, these interventions may lead to needless destruction of the immature transformation zone in young women of low parity.
Don’t neglect counseling, STD testing, birth control
Delaying the first Pap test in young women until 3 years after initial intercourse, however, does not mean we should neglect gynecologic examinations in this group. They are at high risk for sexually transmitted infections and at extremely high risk for unintended pregnancies. So, while waiting 3 years to do the first Pap test makes sense, an early visit, before or soon after first intercourse is essential for gynecologic health care, including prevention of pregnancy and sexually transmitted disease.
October 2004 opinion on Gyn visits for young teens. ACOG published a committee opinion11 to clear up confusion over when adolescent girls should have their first Pap test versus when they should have their first gynecologic visit. The opinion advises a first visit at age 13 to 15, for health guidance, screening, and preventive services, and says parents and patients need to understand that this visit does not necessarily include a pelvic exam or a Pap test. The advisory stresses that adolescents are unlikely to acknowledge sexual activity without sensitive and direct questions, and suggested a resource: “Asking the Right Questions,” from the STD/HTD Prevention Training Center of New England.
AGES 21 TO 30Why is age 21 the “default” for first Pap?
Because the incidence of high-grade squamous intraepithelial lesions (HSIL) increases with age,12 cytology screening should start at age 21, irrespective of sexual history. Saslow et al1 writing for the American Cancer Society, acknowledged the difficulty of obtaining a reliable sexual history. This may be especially true with patients who may have suffered sexual abuse as adolescents. The default age of 21 for initial Pap test allows the provider to sidestep the question of age at first intercourse. On the other hand, a 21-year-old who has never had vaginal intercourse does not need to be screened for cervical cancer.
Aggressive screening until age 30
Women should be screened every year until age 30 if conventional Pap smears are used.1,2 During a woman’s 20s, precancerous lesions become more common and invasive cancer, while still rare, is seen with increasing frequency. Both ACOG and ACS consider this period of a woman’s life to be a time for aggressive cervical cancer screening.
Frequent screening until age 30 allows us to identify and treat young women with histologic cervical intraepithelial neoplasia (CIN) 2 and 3 or worse, and to identify those who, because of persistently negative Pap tests, are at lowest risk.
Since these women schedule more frequent visits for contraception and prenatal care, we have greater opportunities for cervical cancer screening.
Does type of Pap test determine screening interval?
Every 2 years is sufficient if the liquid Pap test is used: ACS.1 This recommendation is based on balancing the increase in abnormal results found with liquid-based Paps against the likelihood that most of the additional abnormal findings will be only atypical squamous cells, undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). These minimally abnormal results, while needing follow-up, have a relatively low rate of CIN 2 or 3 on biopsy.
Annual tests until age 30, irrespective of Pap technology: ACOG.2 That decision recognizes the fact that, while the data suggest increased sensitivity of liquid-based cervical cytology, this observation is not conclusive, and both technologies fall short of 100% sensitivity.
AGES 30 TO 65Why extend the interval between Pap tests?
High risk calls for yearly screens
Both ACOG and the ACS agree that women at high-risk should be screened annually regardless of age.
Risk factors include:
- history of cervical cancer,
- immunocompromise including HIV,
- in utero exposure to diethylstilbestrol (DES), and
- women over age 30 who were not well screened in their 20s; these women should have at least 3 negative annual exams before the screening interval is extended.
Longer interval if risk is low
Up to age 30, frequent screening can be expected to significantly reduce a woman’s risk of cervical cancer. Multiple negative Paps offer a high degree of protection—the more consecutive normal tests, the higher the level of protection.13
Research indicates, however, that it seems reasonable to reduce the screening interval from every year to every 2 to 3 years in previously well-screened women over age 30:
- These women have the protection offered by frequent Pap tests during the previous decade.
- By the time most women reach their 30s, the area of active squamous metaplasia, which serves as the substrate for cervical neoplasia, is reduced.14
Studies of screening effects
National Breast and Cervical Cancer Early Detection Program. Using data from this program, Sawaya et al13 studied 31,728 women aged 30 to 64 with 3 or more consecutive negative Pap tests spaced no more than 3 years apart. They found only 9 women (0.028%) with biopsy-proven CIN 2, only 6 (0.019%) with CIN 3, and none with invasive cancer.
International Agency for Research in Cancer15 data showed essentially no difference in the protective effect of cytology screening at 1-, 2-, or 3-year intervals in women enrolled in screening programs in 7 Western European countries and 3 Canadian centers, among women aged 35 to 64 who had at least 2 previous negative Pap tests. The authors calculated a cumulative reduction in cervical cancer of 93.5% with annual screening, 92.5% with screening every 2 years, and 90.8% with screening every 3 years, compared to women who had no screening.
National Breast and Cervical Cancer Early Detection Program16 data also support extending the screening interval beyond 1 year. In 128,805 women followed after at least 1 prior negative Pap, no significant difference was noted in the incidence of cytologic HSIL on a subsequent Pap performed 9 to 12 months, 13 to 24 months, or 25 to 36 months later. The rates of HSIL were 25, 29, and 33 per 100,000 women, respectively.
Do postmenopausal women need screening?
Women over 65 do get cervical cancer. While they represent 13% of the total U.S. population, they have 25% of new cases of cervical cancer and suffer 41% cervical cancer mortality.17 Incident cases of squamous cancer among older women, however, come from the cohort who have not previously been well screened.
An older woman in a long-term monogamous relationship who has a history of frequent negative Pap tests is at such low risk for acquiring cervical cancer that the US Preventive Services Task Force recommends discontinuing screening in this group at age 65.3
The American Cancer Society recommends discontinuing screening at age 70 in low-risk previously well screened women.1
ACOG does not set a specific upper age for cytology screening.2 While acknowledging the recommendations of these other professional organizations, ACOG notes that there is no good evidence to establish one age over another to discontinue screening, and instead encourages individualization.
ACOG recommends that if an older woman’s sexual practice changes after she is no longer being tested with cytology, some consideration should be given to reinitiating screening. If screening is restarted, 3-year intervals seems appropriate, as older women may have immunity to many HPV types, and their active transformation zone is generally retracted and very narrow.
Why not just continue frequent screening in this less vulnerable population? The consequences of continuing screening in the older, previously well-screened population were nicely illustrated in a study by Sawaya et al,18 using data from the Heart and Estrogen/Progestin Replacement Study (HERS) of postmenopausal women, they evaluated the cytology results of 2,561 women followed over a 4-year period. These women had a Pap test 2 to 2 years after a normal entry cytology.
Subsequent follow-up of cases in which the Pap test was abnormal found only 1 woman with histologic dysplasia, which was a case of mild to moderate dysplasia. To make this diagnosis involved inconvenience, cost and morbidity to the group. To find this single case of mild to moderate dysplasia, 110 women were recalled for follow-ups, which required 231 interventions that included repeat Pap smears, colposcopies, endometrial biopsies, cervical and endocervical biopsies, D&Cs, and excision procedures.
Add to the additional tests, the anxiety inherent in a report of an abnormal Pap test and its follow-up, and the value of limiting screening in this very low risk population become more apparent.
Screen for cervical cancer if there is no cervix?
Since 1996, the US Preventive Services Task Force has recommended against cervical cytology screening in women whose uterus and cervix have been removed for benign indications. Despite this, a recent study showed, as many as 45.6% of such women were still having Pap tests.19
For any screening procedure to be cost effective, there must be a threshold prevalence of the disease in the population to be screened. While women with prior cervical cancer or high-grade dysplasia remain at increased risk for recurrences at the vaginal cuff, women with no history of such disease are at extremely low risk.
In essence, screening in these women becomes a search for primary vaginal cancer, which is one of the rarest of gynecologic malignancies—only 0.3% of cancers in women, a frequency less than that of cancer of the tongue.9 Continued screening in the absence of a cervix implies the need to screen an unacceptably large number of women to diagnose a single lesion. Cytology screening in this group is far more likely to diagnose low-grade vaginal intraepithelial neoplasia (VAIN). VAIN 1 reflects self-limited epithelial changes that are extremely unlikely to progress to cancer.
What is the role of HPV testing?
Last year, the US Food and Drug Administration approved the Hybrid Capture 2 test for high-risk HPV DNA (Digene, Gaithersburg, Md) for use in addition to cervical cytology for screening women over age 30. Both ACOG and the ACS acknowledged this combination of tests as an acceptable option as long as women who test negative on both tests are not retested for 3 years.1,2
Using HPV DNA screening in women under 30 makes little sense. Many studies have confirmed the high prevalence of high-risk HPV in this age group whose risk of invasive cancer is quite low.7,12,20 Screening with HPV before age 30 would result in an unacceptably high false-positive rate, with no advantage over annual screening with cytology alone.
High negative predictive value after age 30
On the other hand, after age 30, as the prevalence of HPV declines, the specificity of this test improves markedly.12 Why wait 3 years before retesting if both tests are negative? The answer lies in the extremely high negative predictive value of the combination. Sherman et al21 determined that the negative predictive value of the combination of cytology plus HPV DNA testing 33 months after both tests are negative is 99.88%. At 45 months, it was still 99.84%.
Thus we can provide excellent assurance to women who test negative that their risk of CIN 3 or squamous cancer is negligible over at least the intervening 3 years.
It’s worth noting that in this same study, the negative predictive value of cytology alone at 33 and 45 months was also quite high: 99.61% and 99.47%, respectively.
ABNORMAL RESULTSConsensus guidelines for combined testing
Management is clear when both tests are negative, or when the Pap shows SIL and the HPV is positive. But what if only 1 of the tests is abnormal? A February 2003 consensus workshop held by ACS, the American Society for Colposcopy and Cervical Pathology, and the National Institutes of Health developed recommendations for managing the various combinations of results.22
ASC-US and positive HPV
Data clearly support triaging these patients to colposcopy. The National Cancer Institute’s ASCUS/LSIL Triage study (ALTS) study showed that, in a group of 1,161 women, this combination of results had a 92% sensitivity for diagnosing CIN 3.23 Solomon Other studies, done under perhaps less rigorous scientific conditions, also showed high sensitivity, though generally not as high as in the ALTS study.
When cytology results are more severe than ASC-US
If results are ASC-H, AGC, LSIL, or HSIL, manage with colposcopy regardless of HPV results.
Negative cytology and positive for high-risk HPV
This scenario is more difficult for both the physician and patient. High-risk HPV is a clear risk factor for subsequent dysplasia.21 While most HPV infections are transient, the risk of dysplasia increases when they persist.24 A reasonable course is to repeat both Pap and HPV in 6 to 12 months. This allows time for transient HPV infections to clear and for persistent infections to be identified on the repeat test.
The ultimate prognosis and management are determined by the repeat cytology plus HPV. If both repeat tests are negative, further repeat screening should be delayed for 3 years.
If the cytology is ASC-US, but HPV is negative, the patient may safely be screened again in 1 year with Pap plus HPV. Colposcopy is indicated if the cytology is worse than ASC-US and/or if the HPV remains positive.
Counseling HPV-positive patients
Perhaps the most difficult aspect of screening with cytology plus HPV DNA is what to advise patients whose Pap test is normal but whose HPV is positive.
Many women are aware that HPV is sexually transmitted, and a positive HPV test conjures fears of spousal infidelity, concerns about spreading the infection, and fear of other sexually transmitted infections.
Long latency. I have found it useful to defuse the infidelity concern by pointing to the long latent period associated with HPV infections. A recently diagnosed HPV infection may have been acquired years in the past from a prior partner, or from her current partner early in their relationship.
Neither partner should construe a positive test for high-risk HPV as an indicator of promiscuity. It is just as likely that a temporary change in her immune status allowed a previously latent infection to become productive.
Highly prevalent. The patient may be reassured by knowing that HPV is exceedingly common; up to 75% of women will have one or more subtypes of HPV in their lower genital tract at some time in their lives. Pointing out that it can be considered a marker of ever having had vaginal intercourse may help to eliminate the stigma of a sexually transmitted disease.
Let her know her partner probably carries the same HPV type, or has cleared it in the past.
Low risk of cancer for the partner. Male partners of women who test positive for high-risk HPV DNA do not require any testing. Reassure the couple that the male’s risk of cancer is very low since the penis lacks a transformation zone, the substrate for efficient neoplastic transformation.
Reassure her of low risk without neoplastic changes. The presence of HPV on the cervix is of little clinical importance unless the cervical epithelium has begun to undergo neoplastic changes. Reassure the patient that as long as she has no squamous intraepithelial lesions on Pap testing or a persistently positive HPV DNA test over time, she has a low risk developing cancer.
What’s the harm in yearly testing?
Will our patients skip annual gynecologic exams if we tell them they no longer need an annual Pap test? If Paps are performed only every 3 years, will many women wait 4 or 5 years between screenings?
These and other concerns make it difficult to change an ingrained routine, despite data that support new practice guidelines.
Besides, the Pap test is inexpensive, so what’s the harm in doing it annually? While the Pap test itself remains relatively inexpensive, the wide popularity of the liquid-based Pap test has doubled or tripled the cost of the test in many markets. And annual testing in low-risk women has a high rate of false positives, which require costly follow-up testing.13
Though future studies must determine the optimal interval for gynecologic examinations in asymptomatic women, periodic examinations are certainly important—even if a Pap test is not done each year. As primary-care providers, gynecologists offer periodic screenings for conditions such as diabetes, cardiac disease, and colon cancer, in addition to gynecologic evaluations. And it makes good sense to encourage frequent periodic exams for patients at risk, such as young women in need of contraceptive counseling or evaluation for sexually transmitted disease, and older women in need of breast surveillance.
But if we provide periodic screening without the “Pap-smear prompt,” we’ll need to redouble our efforts to teach patients the value of the annual exam for other health assessments, not cervical cytology screening alone.
The authors report no relevant financial relationships.
1. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guidelines for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. November-December 2002;52:342-362.
2. American College of Obstetricians and Gynecologists. Practice bulletin No. 45: cervical cytology screening. Obstet Gynecol. 2003;102:417-427.
3. US Preventative Services Task Force. Screening for cervical cancer. Rockville, Md: Agency for Healthcare Research and Quality; 2003. Available at: http://www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanwh.pdf. Accessed November 1, 2004.
4. American College of Obstetricians and Gynecologists. Technical bulletin No. 29: the frequency with which a cervical-vaginal cytology examination should be performed in gynecologic practice. Washington, DC: ACOG; February 1975.
5. Muñoz N, Bosch X, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Eng J Med. 2003;348:518-527.
6. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19.
7. Ho GY, Bierman R, Beardsley L, et al. The natural history of cervical papillomavirus infection in young women. N Engl J Med. 1998;338:423-428.
8. Moscicki AB, Shiboski S., Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277-284.
9. Moscicki AB. Cervical cytology screening in teens. Curr Womens Health Rep. 2003;3:433-437.
10. Reis LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975-2001. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2001/. Accessed November 8, 2004.
11. American College of Obstetricians and Gynecologists. Committee opinion No. 300: cervical cancer screening in adolescents. Obstet Gynecol. 2004;104:885-889.
12. Kulasingam SL, Hughes JP, Kiviat NB, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288:1749-1757.
13. Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
14. Moscicki AB, Burt VG, Kanowitz S, et al. The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. Cancer. 1999;85:1139-1144.
15. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed). 1986;293:659-664.
16. Sawaya GF, Kerlikowske K, Lee NC, et al. Frequency of cervical smear abnormalities within 3 years of normal cytology. Obstet Gyncol. 2000;96:219-223.
17. NIH Consensus statement: cervical cancer. National Institutes of Health. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, 1996;14:1-38.
18. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/Progestin Replacement Study (HERS). Ann Intern Med. 2000;133:942-950.
19. Sirovich BE, Welch HG. Cervical cancer screening among women without a cervix. JAMA. 2004;291:2990-2993.
20. Sellors JW, Karwalajtys TL, Kaczorowski JA, et al. Prevalence of infection with carcinogenic human papillomavirus among older women. CMAJ. 2002;167:871-873.
21. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46-52.
22. Wright TC, Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-309.
23. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383-1392.
24. Schlect NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA. 2001;286:3106-3114.
1. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guidelines for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. November-December 2002;52:342-362.
2. American College of Obstetricians and Gynecologists. Practice bulletin No. 45: cervical cytology screening. Obstet Gynecol. 2003;102:417-427.
3. US Preventative Services Task Force. Screening for cervical cancer. Rockville, Md: Agency for Healthcare Research and Quality; 2003. Available at: http://www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanwh.pdf. Accessed November 1, 2004.
4. American College of Obstetricians and Gynecologists. Technical bulletin No. 29: the frequency with which a cervical-vaginal cytology examination should be performed in gynecologic practice. Washington, DC: ACOG; February 1975.
5. Muñoz N, Bosch X, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Eng J Med. 2003;348:518-527.
6. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19.
7. Ho GY, Bierman R, Beardsley L, et al. The natural history of cervical papillomavirus infection in young women. N Engl J Med. 1998;338:423-428.
8. Moscicki AB, Shiboski S., Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277-284.
9. Moscicki AB. Cervical cytology screening in teens. Curr Womens Health Rep. 2003;3:433-437.
10. Reis LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975-2001. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2001/. Accessed November 8, 2004.
11. American College of Obstetricians and Gynecologists. Committee opinion No. 300: cervical cancer screening in adolescents. Obstet Gynecol. 2004;104:885-889.
12. Kulasingam SL, Hughes JP, Kiviat NB, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288:1749-1757.
13. Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501-1509.
14. Moscicki AB, Burt VG, Kanowitz S, et al. The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women. Cancer. 1999;85:1139-1144.
15. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed). 1986;293:659-664.
16. Sawaya GF, Kerlikowske K, Lee NC, et al. Frequency of cervical smear abnormalities within 3 years of normal cytology. Obstet Gyncol. 2000;96:219-223.
17. NIH Consensus statement: cervical cancer. National Institutes of Health. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, 1996;14:1-38.
18. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/Progestin Replacement Study (HERS). Ann Intern Med. 2000;133:942-950.
19. Sirovich BE, Welch HG. Cervical cancer screening among women without a cervix. JAMA. 2004;291:2990-2993.
20. Sellors JW, Karwalajtys TL, Kaczorowski JA, et al. Prevalence of infection with carcinogenic human papillomavirus among older women. CMAJ. 2002;167:871-873.
21. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46-52.
22. Wright TC, Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-309.
23. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383-1392.
24. Schlect NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA. 2001;286:3106-3114.
VBAC: When is it safe?
- Selection criteria useful for identifying candidates for VBAC include: a limit of 1 prior low-transverse cesarean, clinically adequate pelvis, no other uterine scars or previous rupture, and no contraindications.
- Offer VBAC only if obstetric care and anesthesiology are available throughout active labor, in case emergency cesarean is necessary.
- Single-layer uterine closure may increase the risk of rupture during subsequent labors.
- Epidural anesthesia is safe for women undergoing a trial of labor.
The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.
VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.2
Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,3 but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.
Recent studies of risks and benefits
No randomized trials. ACOG notes,1 “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”
Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.4-6
Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.7-9
Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.10-17
When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.3,4,9
Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.3,8,9,18
Indications and contraindications
The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.
Don’t assume: Check the previous operative note
It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.
While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.
For these reasons, review the actual operative report whenever possible before a trial of labor.
2 prior low-transverse incisions
While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.
Prior low-vertical incision
Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.20,21
Greater risk with single-layer closure
Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.22 As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.22
Discourage closely spaced gestations
The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.
Labor induction increases risk
Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.25
The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.26 ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.26
Seek out other factors
Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.15,26-28
External cephalic version. Although 1 study29 concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.
Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.30,31
Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.27
Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.11
Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.1
Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.34,35
Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.
TABLE
Criteria for trial of labor
| QUALIFICATIONS |
| 1 prior low-transverse cesarean section |
| Clinically adequate pelvis |
| No other uterine scars |
| DISQUALIFICATIONS |
| Prior classical or T-shaped uterine incision |
| Multiple uterine incisions |
| Previous uterine rupture |
| Contracted pelvis |
| Contraindications to vaginal birth |
| REQUIREMENTS THROUGHOUT ACTIVE LABOR |
| Obstetrician immediately available |
| Continuous electronic monitoring of the fetal heart rate |
| Personnel skilled in interpreting fetal tracings |
| Anesthesia for emergency cesarean |
| Physician qualified for emergency cesarean |
| PRECAUTIONS |
| Unknown uterine scars |
| Prior low vertical uterine incision |
| Uterine malformations |
| Prior single-layer uterine closure |
| Short interdelivery interval |
| Need for labor induction |
| Need for external cephalic version |
| Twin gestation |
| Suspected macrosomia |
| Maternal obesity |
| Postdates |
| Advanced maternal age |
| No prior vaginal delivery |
| Source: ACOG1 |
Prognostic formulas
One decision analysis36 concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)
CASE 1
A single cesarean and a healthy fetus
After her obstetrician encourages a repeat cesarean at 39 weeks’ gestation, a 39-year-old gravida seeks a second opinion. Her obstetric history includes a remote first-trimester miscarriage and a cesarean section, 2 years prior, of vertex-vertex twins at 36 weeks for arrest of labor at 8 cm. Tubal ligation is planned after delivery.
The previous operative report indicates that a low-transverse uterine incision was repaired in 2 layers. The patient plans to deliver at a local community hospital without full-time, in-hospital anesthesiology services.
This pregnancy has been uncomplicated, and ultrasound has confirmed a normally grown fetus in vertex presentation with a fundal placenta. The patient is considering vaginal birth after cesarean (VBAC).
Decision Multiple factors make VBAC unwise
This patient is a poor candidate due to advanced maternal age, no prior vaginal birth, and the previous cesarean for failure to progress. Lack of round-the-clock anesthesiology at her chosen hospital contraindicates trial of labor.1
Her request for postpartum sterilization also makes repeat cesarean wiser.
After these risks are explained, the patient accepts the recommendation for elective repeat cesarean.
CASE 2
Breech presentation, short interdelivery interval
A 28-year-old gravida has a breech presentation at 37 weeks. She has had 3 spontaneous vaginal deliveries and 1 cesarean section at term for a nonreassuring fetal tracing in labor. The cesarean was 14 months ago. The operative note is not available. She says she was told future vaginal deliveries would be possible.
She plans to have a large family.
Apart from the breech presentation, this pregnancy has been uneventful. The patient requests external cephalic version prior to a trial of labor.
Decision Take future plans into account
Placenta previa, accreta, adhesions, and intraoperative injuries are recognized risks in patients with a higher number of cesarean deliveries.
In this case, breech presentation, a short interdelivery interval, and an undocumented uterine incision warrant caution. Given that the patient’s cesarean section was performed at term in the United States, and that she was told she would be able to have a subsequent vaginal birth, she underwent a successful external cephalic version in the delivery room. She had an uneventful spontaneous vaginal delivery 3 weeks later.
CASE 3
Good candidate, nervous about risk
A 30-year-old woman with 1 uncomplicated vaginal delivery and 1 cesarean section 3 years prior presents in her third pregnancy for counseling about VBAC.
Her cesarean was performed through a transverse incision in the lower uterine segment for repetitive deep variable decelerations. A friend recently experienced uterine rupture during a trial of labor, resulting in a hysterectomy. She is undecided about future childbearing.
Decision Patient and physician agree on cesarean
With a prior vaginal delivery and a previous cesarean through a low-transverse uterine incision over 18 months ago for an indication that is unlikely to recur, the likelihood of VBAC success is high.
However, the patient was worried by potential risks for uterine rupture, adverse perinatal outcome, and loss of future reproductive potential. After considering the risks and benefits, she requested a repeat cesarean delivery.
After fully counseling the patient on the risks and benefits of VBAC versus elective repeat cesarean, a management plan was made and documented.
The patient underwent an uncomplicated cesarean section at 39 weeks and delivered a healthy baby.
VBAC is not an option where facilities fall short
Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.1 As a result, many midwives and family practitioners can no longer care for VBAC patients independently.
Continuous monitoring is a must
It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.1 Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.1
Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.
Also crucial: Anesthesiology
ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.1 While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option
Reducing medicolegal risk
When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include37:
- Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
- A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
- If possible, documentation of previous uterine scar on the prenatal record.
- Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
- Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
- Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
Is VBAC availability better for health and happiness?
Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.38 When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.
Risk of placenta accreta
If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.
Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.41 As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.42
For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.
Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.
I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.
Should we abandon VBAC?
An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.
What exactly is the risk of rupture?
In 1 population-based, retrospective cohort analysis25 involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.
In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.25
Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.
Perinatal death more likely with VBAC, but absolute risk is low
A separate population-based, retrospective, cohort study18 focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.
Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.18
What’s the bottom line?
Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis43 of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.
A more recent meta-analysis9 of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.6
Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.44
Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.
The author reports no relevant financial relationships.
1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin #54: Vaginal Birth After Previous Cesarean Delivery. Washington, DC: ACOG; July 2004.
2. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep. 2003;52(10):1-113.
3. Rageth JC, Juzi C, Grossenbacher H. for the Swiss Working Group of Obstetric and Gynecologic Institutions. Delivery after previous cesarean: a risk evaluation. Obstet Gynecol. 1999;93:332-337.
4. Hibbard JU, Ismail MA, Wang Y, Te C, Karrison T, Ismail MA. Failed vaginal birth after a cesarean section: how risky is it? I. Maternal morbidity. Am J Obstet Gynecol. 2001;184:1365-1371;discussion 1371–1373.
5. Bujold E, Gauthier RJ. Should we allow a trial of labor after a previous cesarean for dystocia in the second stage of labor? Obstet Gynecol. 2001;98:652-655.
6. Chauhan SP, Martin JN, Jr, Henrichs CE, Morrison JC, Magann EF. Maternal and perinatal complications with uterine rupture in 142,075 patients who attempted vaginal birth after cesarean delivery: a review of the literature. Am J Obstet Gynecol. 2003;189:408-417.
7. Gregory KD, Korst LM, Cane P, Platt LD, Kahn K. Vaginal birth after cesarean and uterine rupture rates in California. Obstet Gynecol. 1999;94:985-989.
8. Kieser KE, Baskett TF. A 10-year population-based study of uterine rupture. Obstet Gynecol. 2002;100:749-753.
9. Mozurkewich EL, Hutton EK. Elective repeat cesarean delivery versus trial of labor: a meta-analysis of the literature from 1989 to 1999. Am J Obstet Gynecol. 2000;183:1187-1197.
10. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Outcomes of a trial of labor following previous cesarean delivery among women with fetuses weighing >4,000 g. Am J Obstet Gynecol. 2001;185:903-905.
11. Zelop CM, Shipp TD, Cohen A, Repke JT, Lieberman E. Trial of labor after 40 weeks’ gestation in women with prior cesarean. Obstet Gynecol. 2001;97:391-393.
12. Macones GA, Hausman N, Edelstein R, Stamilio DM, Marder SJ. Predicting outcomes of trials of labor in women attempting vaginal birth after cesarean delivery: a comparison of multivariate methods with neural networks. Am J Obstet Gynecol. 2001;184:409-413.
13. Ravasia DJ, Wood SL, Pollard JK. Uterine rupture during induced trial of labor among women with previous cesarean delivery. Am J Obstet Gynecol. 2000;183:1176-1179.
14. Sims EJ, Newman RB, Hulsey TC. Vaginal birth after cesarean: to induce or not to induce. Am J Obstet Gynecol. 2001;184:1122-1124.
15. Chauhan SP, Magann EF, Carroll CS, Barrilleaux PS, Scardo JA, Marttin JN, Jr. Mode of delivery for the morbidly obese with prior cesarean delivery: vaginal versus repeat cesarean section. Am J Obstet Gynecol. 2001;185:349-354.
16. Carroll CS, Sr, Magann EF, Chauhan SP, Klauser CK, Morrison JC. Vaginal birth after cesarean section versus elective repeat cesarean delivery: weight-based outcomes. Am J Obstet Gynecol. 2003;188:1516-1520;discussion 1520–1522.
17. Huang WH, Nakashima DK, Rumney PJ, Keegan KA, Jr, Chan K. Interdelivery interval and the success of vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:41-44.
18. Smith GC, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA. 2002;287:2684-2690.
19. Bretelle F, Cravello L, Shojai R, Roger V, D’Ercole C, Blanc B. Vaginal birth following two previous cesarean sections. Eur J Obstet Gynecol Reprod Biol. 2001;94:23-26.
20. Shipp TD, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Intrapartum uterine rupture and dehiscence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol. 1999;94:735-740.
21. Naef RW, Ray MA, Chauhan SP, Roach H, Blake PG, Martin JN. Trial of labor after cesarean delivery with a lower-segment, vertical uterine incision: is it safe? Am J Obstet Gynecol. 1995;172:1666-1673.
22. Bujold E, Mehta SH, Bujold C, Gauthier RJ. Interdelivery interval and uterine rupture. Am J Obstet Gynecol. 2002;187:1199-1202.
23. Shipp TD, Zelop CM, Repke JT, Cohen A, Lieberman E. Interdelivery interval and risk of symptomatic uterine rupture. Obstet Gynecol. 2001;97:175-177.
24. Esposito MA, Menihan CA, Malee MP. Association of interpregnancy interval with uterine scar failure in labor: a case control study. Am J Obstet Gynecol. 2000;183:1180-1183.
25. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med. 2001;345:3-8.
26. American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. Committee Opinion: Induction of labor for vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:679-680.
27. Elkousy MA, Sammel M, Stevens E, Peipert JF, Macones G. The effect of birth weight on vaginal birth after cesarean delivery success rates. Am J Obstet Gynecol. 2003;188:824-830.
28. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Effects of previous vaginal delivery on the risk of uterine rupture during a subsequent trial of labor. Am J Obstet Gynecol. 2000;183:1184-1186.
29. Flamm BL, Fried MW, Lonky NM, Giles WS. External cephalic version after previous cesarean section. Am J Obstet Gynecol. 1991;165:370-372.
30. Myles T. Vaginal birth of twins after a previous cesarean section. J Matern Fetal Med. 2001;10:171-174.
31. Sansregret A, Bujold E, Gauthier RJ. Twin delivery after a previous cesarean: a 12-year experience. J Obstet Gynaecol Can. 2003;25:294-298.
32. Johnson C, Oriol N. The role of epidural anesthesia in trial of labor. Reg Anesth. 1990;15:304-308.
33. Sakala EP, Kaye S, Murray RD, Munson LJ. Epidural analgesia. Effect on the likelihood of a successful trial of labor after cesarean section. J Reprod Med. 1990;35:886-890.
34. Flamm BL. Once a cesarean, always a controversy. Obstet Gynecol. 1997;90:312-315.
35. McNally OM, Turner MJ. Induction of labor after 1 previous caesarean section. Aust N Z J Obstet Gynaecol. 1999;39:425-429.
36. Mankuta DD, Leshno MM, Menasche MM, Brezis MM. Vaginal birth after cesarean section: trial of labor or repeat cesarean section? A decision analysis. Am J Obstet Gynecol. 2003;189:714-719.
37. Martel MJ, MacKinnon CJ. Clinical Practice Obstetrics Committee of the Society of Obstetricians and Gynaecologists of Canada. Guidelines for vaginal birth after previous Caesarean birth. J Obstet Gynaecol Can. 2004;26:660-683.
38. McMahon MJ, Luther ER, Bowes WA, Olshan AF. Comparison of a trial of labor with an elective second section. N Engl J Med. 1996;335:689-695.
39. Ananth CV, Smulian JC, Vintzileos AM. The association of placenta previa with history of cesarean delivery and abortion: a metaanalysis. Am J Obstet Gynecol. 1997;177:1071-1078.
40. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa-placenta accreta. Am J Obstet Gynecol. 1997;177:210-214.
41. Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarean section. Obstet Gynecol. 1985;66:89-92.
42. O’Brien JM, Barton JR, Donaldson ES. The management of placenta percreta: conservative and operative strategies. Am J Obstet Gynecol. 1996;175:1632-1638.
43. Rosen MG, Dickinson JC, Westhoff CL. Vaginal birth after cesarean: a meta-analysis of morbidity and mortality. Obstet Gynecol. 1991;77:465-470.
44. Hall MH, Bewley S. Maternal mortality and mode of delivery. Lancet. 1999;354:776.-
- Selection criteria useful for identifying candidates for VBAC include: a limit of 1 prior low-transverse cesarean, clinically adequate pelvis, no other uterine scars or previous rupture, and no contraindications.
- Offer VBAC only if obstetric care and anesthesiology are available throughout active labor, in case emergency cesarean is necessary.
- Single-layer uterine closure may increase the risk of rupture during subsequent labors.
- Epidural anesthesia is safe for women undergoing a trial of labor.
The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.
VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.2
Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,3 but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.
Recent studies of risks and benefits
No randomized trials. ACOG notes,1 “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”
Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.4-6
Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.7-9
Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.10-17
When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.3,4,9
Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.3,8,9,18
Indications and contraindications
The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.
Don’t assume: Check the previous operative note
It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.
While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.
For these reasons, review the actual operative report whenever possible before a trial of labor.
2 prior low-transverse incisions
While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.
Prior low-vertical incision
Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.20,21
Greater risk with single-layer closure
Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.22 As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.22
Discourage closely spaced gestations
The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.
Labor induction increases risk
Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.25
The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.26 ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.26
Seek out other factors
Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.15,26-28
External cephalic version. Although 1 study29 concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.
Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.30,31
Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.27
Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.11
Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.1
Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.34,35
Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.
TABLE
Criteria for trial of labor
| QUALIFICATIONS |
| 1 prior low-transverse cesarean section |
| Clinically adequate pelvis |
| No other uterine scars |
| DISQUALIFICATIONS |
| Prior classical or T-shaped uterine incision |
| Multiple uterine incisions |
| Previous uterine rupture |
| Contracted pelvis |
| Contraindications to vaginal birth |
| REQUIREMENTS THROUGHOUT ACTIVE LABOR |
| Obstetrician immediately available |
| Continuous electronic monitoring of the fetal heart rate |
| Personnel skilled in interpreting fetal tracings |
| Anesthesia for emergency cesarean |
| Physician qualified for emergency cesarean |
| PRECAUTIONS |
| Unknown uterine scars |
| Prior low vertical uterine incision |
| Uterine malformations |
| Prior single-layer uterine closure |
| Short interdelivery interval |
| Need for labor induction |
| Need for external cephalic version |
| Twin gestation |
| Suspected macrosomia |
| Maternal obesity |
| Postdates |
| Advanced maternal age |
| No prior vaginal delivery |
| Source: ACOG1 |
Prognostic formulas
One decision analysis36 concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)
CASE 1
A single cesarean and a healthy fetus
After her obstetrician encourages a repeat cesarean at 39 weeks’ gestation, a 39-year-old gravida seeks a second opinion. Her obstetric history includes a remote first-trimester miscarriage and a cesarean section, 2 years prior, of vertex-vertex twins at 36 weeks for arrest of labor at 8 cm. Tubal ligation is planned after delivery.
The previous operative report indicates that a low-transverse uterine incision was repaired in 2 layers. The patient plans to deliver at a local community hospital without full-time, in-hospital anesthesiology services.
This pregnancy has been uncomplicated, and ultrasound has confirmed a normally grown fetus in vertex presentation with a fundal placenta. The patient is considering vaginal birth after cesarean (VBAC).
Decision Multiple factors make VBAC unwise
This patient is a poor candidate due to advanced maternal age, no prior vaginal birth, and the previous cesarean for failure to progress. Lack of round-the-clock anesthesiology at her chosen hospital contraindicates trial of labor.1
Her request for postpartum sterilization also makes repeat cesarean wiser.
After these risks are explained, the patient accepts the recommendation for elective repeat cesarean.
CASE 2
Breech presentation, short interdelivery interval
A 28-year-old gravida has a breech presentation at 37 weeks. She has had 3 spontaneous vaginal deliveries and 1 cesarean section at term for a nonreassuring fetal tracing in labor. The cesarean was 14 months ago. The operative note is not available. She says she was told future vaginal deliveries would be possible.
She plans to have a large family.
Apart from the breech presentation, this pregnancy has been uneventful. The patient requests external cephalic version prior to a trial of labor.
Decision Take future plans into account
Placenta previa, accreta, adhesions, and intraoperative injuries are recognized risks in patients with a higher number of cesarean deliveries.
In this case, breech presentation, a short interdelivery interval, and an undocumented uterine incision warrant caution. Given that the patient’s cesarean section was performed at term in the United States, and that she was told she would be able to have a subsequent vaginal birth, she underwent a successful external cephalic version in the delivery room. She had an uneventful spontaneous vaginal delivery 3 weeks later.
CASE 3
Good candidate, nervous about risk
A 30-year-old woman with 1 uncomplicated vaginal delivery and 1 cesarean section 3 years prior presents in her third pregnancy for counseling about VBAC.
Her cesarean was performed through a transverse incision in the lower uterine segment for repetitive deep variable decelerations. A friend recently experienced uterine rupture during a trial of labor, resulting in a hysterectomy. She is undecided about future childbearing.
Decision Patient and physician agree on cesarean
With a prior vaginal delivery and a previous cesarean through a low-transverse uterine incision over 18 months ago for an indication that is unlikely to recur, the likelihood of VBAC success is high.
However, the patient was worried by potential risks for uterine rupture, adverse perinatal outcome, and loss of future reproductive potential. After considering the risks and benefits, she requested a repeat cesarean delivery.
After fully counseling the patient on the risks and benefits of VBAC versus elective repeat cesarean, a management plan was made and documented.
The patient underwent an uncomplicated cesarean section at 39 weeks and delivered a healthy baby.
VBAC is not an option where facilities fall short
Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.1 As a result, many midwives and family practitioners can no longer care for VBAC patients independently.
Continuous monitoring is a must
It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.1 Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.1
Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.
Also crucial: Anesthesiology
ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.1 While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option
Reducing medicolegal risk
When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include37:
- Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
- A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
- If possible, documentation of previous uterine scar on the prenatal record.
- Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
- Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
- Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
Is VBAC availability better for health and happiness?
Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.38 When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.
Risk of placenta accreta
If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.
Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.41 As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.42
For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.
Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.
I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.
Should we abandon VBAC?
An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.
What exactly is the risk of rupture?
In 1 population-based, retrospective cohort analysis25 involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.
In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.25
Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.
Perinatal death more likely with VBAC, but absolute risk is low
A separate population-based, retrospective, cohort study18 focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.
Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.18
What’s the bottom line?
Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis43 of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.
A more recent meta-analysis9 of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.6
Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.44
Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.
The author reports no relevant financial relationships.
- Selection criteria useful for identifying candidates for VBAC include: a limit of 1 prior low-transverse cesarean, clinically adequate pelvis, no other uterine scars or previous rupture, and no contraindications.
- Offer VBAC only if obstetric care and anesthesiology are available throughout active labor, in case emergency cesarean is necessary.
- Single-layer uterine closure may increase the risk of rupture during subsequent labors.
- Epidural anesthesia is safe for women undergoing a trial of labor.
The new bulletin reaffirms the previous recommendation that obstetric and anesthesia personnel be immediately available throughout active labor, in case emergency cesarean is necessary.
VBAC is still within the standard of care, but rates were declining even before the new bulletin was released: from a high of 28.3% in 1996 to 12.6% in 2002.2
Benefits of VBAC may outweigh the risks in most women with 1 previous low-transverse cesarean,3 but even with optimal facilities and personnel, numerous factors warrant special caution, according to recent studies I’ll review in this article.
Recent studies of risks and benefits
No randomized trials. ACOG notes,1 “Despite thousands of citations in the world’s literature, there are currently no randomized trials comparing maternal or neonatal outcomes for both repeat cesarean delivery and VBAC.”
Success rates are similar for gravidas with previous cesarean for a nonrecurring indication and those with no previous cesarean.4-6
Uterine rupture is more likely during a trial of labor, but the rate is usually below 1%.7-9
Other limiting factors may include labor augmentation and induction, maternal obesity, gestational age beyond 40 weeks, birth weight over 4,000 g, and an interdelivery interval of less than 19 months.10-17
When a trial of labor fails, women face a heightened risk of uterine rupture, hysterectomy, transfusion, and endometritis.3,4,9
Perinatal death is more likely during VBAC than planned repeat cesarean, although the death rate is usually less than 1%.3,8,9,18
Indications and contraindications
The TABLE outlines potential candidates, ineligible gravidas, resources needed, and situations that warrant caution.
Don’t assume: Check the previous operative note
It is all too easy to presume that a previous cesarean section at term was performed through a transverse incision in the lower uterine segment.
While this may be true in the majority of cases, the actual operative note may reveal information relevant to the delivery decision: an extensive tear of the uterine incision, previously unrecognized uterine anomalies, or the need to perform a classical or T-shaped incision to facilitate delivery of the infant.
For these reasons, review the actual operative report whenever possible before a trial of labor.
2 prior low-transverse incisions
While this is not an absolute contraindication to VBAC, in today’s cautious climate ACOG recommends VBAC proceed only when there is also a history of successful vaginal delivery.1,19 Otherwise, women with 2 or more previous cesareans should undergo repeat abdominal birth.
Prior low-vertical incision
Although successful VBACs have been reported in women with a prior low-vertical uterine incision, many experts feel that these incisions often extend superiorly into the upper uterus and thus increase the likelihood of uterine rupture in subsequent labors.20,21
Greater risk with single-layer closure
Single-layer uterine closure appears to increase the likelihood of rupture during subsequent labors.22 As a result, many physicians have returned to 2-layer closure of the lower transverse uterine incision. It is unclear whether single-layer closure is a contraindication to subsequent labor, but it does warrant caution due to a 4-fold increase in the risk of rupture.22
Discourage closely spaced gestations
The shorter the interval between deliveries, the more likely is uterine rupture during a trial of labor.23,24 For those considering a subsequent VBAC, I recommend trying to space their next delivery at least 18 months after cesarean birth.
Labor induction increases risk
Spontaneous labor leads to successful VBAC more often than does labor induction or augmentation. In addition, a recent study found 5 times the risk of uterine rupture when oxytocin was used to induce labor, compared with elective repeat cesarean—although the rate of rupture was less than 1% in both groups.25
The use of prostaglandins in labor induction greatly increases the risk of rupture, with rates of 24.5 per 1,000 reported, compared with 5.2 per 1,000 in women with spontaneous labor.26 ACOG strongly discourages the use of prostaglandin cervical ripening agents in labor inductions.26
Seek out other factors
Women who initially appear eligible may harbor other characteristics or conditions that warrant special attention.15,26-28
External cephalic version. Although 1 study29 concluded it is effective in women undergoing a trial of labor after cesarean, vigilance is recommended.
Twin gestations. Two retrospective studies involving a total of 45 women found VBAC to be safe in twin gestations. Because of the limited number of women studied and the lack of randomized, controlled trials, caution is strongly advised.30,31
Macrosomia. The rate of uterine rupture rises in women who have not had a previous vaginal delivery.27
Postdates. Although VBAC is less likely to succeed after 40 weeks’ gestation, the risk of uterine rupture increases only with induction of labor.11
Analgesia. Women undergoing a trial of labor can receive epidural anesthesia without increasing the risk of rupture or failed VBAC and without obscuring the signs and symptoms of uterine rupture.32,33 In fact, as ACOG notes, effective pain relief may encourage more women to try VBAC.1
Previous vaginal delivery. Women who have delivered vaginally are more likely to succeed at VBAC—by a factor of 9 to 28—than those who have not.34,35
Other conditions such as maternal obesity and advanced age should be evaluated in light of the patient’s overall risk-benefit profile. Although caution is recommended, definitive data are lacking.
TABLE
Criteria for trial of labor
| QUALIFICATIONS |
| 1 prior low-transverse cesarean section |
| Clinically adequate pelvis |
| No other uterine scars |
| DISQUALIFICATIONS |
| Prior classical or T-shaped uterine incision |
| Multiple uterine incisions |
| Previous uterine rupture |
| Contracted pelvis |
| Contraindications to vaginal birth |
| REQUIREMENTS THROUGHOUT ACTIVE LABOR |
| Obstetrician immediately available |
| Continuous electronic monitoring of the fetal heart rate |
| Personnel skilled in interpreting fetal tracings |
| Anesthesia for emergency cesarean |
| Physician qualified for emergency cesarean |
| PRECAUTIONS |
| Unknown uterine scars |
| Prior low vertical uterine incision |
| Uterine malformations |
| Prior single-layer uterine closure |
| Short interdelivery interval |
| Need for labor induction |
| Need for external cephalic version |
| Twin gestation |
| Suspected macrosomia |
| Maternal obesity |
| Postdates |
| Advanced maternal age |
| No prior vaginal delivery |
| Source: ACOG1 |
Prognostic formulas
One decision analysis36 concluded that VBAC is a reasonable option when the chance of success exceeds 50% and the desire for future pregnancy is 10% to 20% or more. Although scoring systems have been proposed to predict the likelihood of success, individualized assessment of each patient is ideal. (See “Case by case: Adding up the decisive factors”.)
CASE 1
A single cesarean and a healthy fetus
After her obstetrician encourages a repeat cesarean at 39 weeks’ gestation, a 39-year-old gravida seeks a second opinion. Her obstetric history includes a remote first-trimester miscarriage and a cesarean section, 2 years prior, of vertex-vertex twins at 36 weeks for arrest of labor at 8 cm. Tubal ligation is planned after delivery.
The previous operative report indicates that a low-transverse uterine incision was repaired in 2 layers. The patient plans to deliver at a local community hospital without full-time, in-hospital anesthesiology services.
This pregnancy has been uncomplicated, and ultrasound has confirmed a normally grown fetus in vertex presentation with a fundal placenta. The patient is considering vaginal birth after cesarean (VBAC).
Decision Multiple factors make VBAC unwise
This patient is a poor candidate due to advanced maternal age, no prior vaginal birth, and the previous cesarean for failure to progress. Lack of round-the-clock anesthesiology at her chosen hospital contraindicates trial of labor.1
Her request for postpartum sterilization also makes repeat cesarean wiser.
After these risks are explained, the patient accepts the recommendation for elective repeat cesarean.
CASE 2
Breech presentation, short interdelivery interval
A 28-year-old gravida has a breech presentation at 37 weeks. She has had 3 spontaneous vaginal deliveries and 1 cesarean section at term for a nonreassuring fetal tracing in labor. The cesarean was 14 months ago. The operative note is not available. She says she was told future vaginal deliveries would be possible.
She plans to have a large family.
Apart from the breech presentation, this pregnancy has been uneventful. The patient requests external cephalic version prior to a trial of labor.
Decision Take future plans into account
Placenta previa, accreta, adhesions, and intraoperative injuries are recognized risks in patients with a higher number of cesarean deliveries.
In this case, breech presentation, a short interdelivery interval, and an undocumented uterine incision warrant caution. Given that the patient’s cesarean section was performed at term in the United States, and that she was told she would be able to have a subsequent vaginal birth, she underwent a successful external cephalic version in the delivery room. She had an uneventful spontaneous vaginal delivery 3 weeks later.
CASE 3
Good candidate, nervous about risk
A 30-year-old woman with 1 uncomplicated vaginal delivery and 1 cesarean section 3 years prior presents in her third pregnancy for counseling about VBAC.
Her cesarean was performed through a transverse incision in the lower uterine segment for repetitive deep variable decelerations. A friend recently experienced uterine rupture during a trial of labor, resulting in a hysterectomy. She is undecided about future childbearing.
Decision Patient and physician agree on cesarean
With a prior vaginal delivery and a previous cesarean through a low-transverse uterine incision over 18 months ago for an indication that is unlikely to recur, the likelihood of VBAC success is high.
However, the patient was worried by potential risks for uterine rupture, adverse perinatal outcome, and loss of future reproductive potential. After considering the risks and benefits, she requested a repeat cesarean delivery.
After fully counseling the patient on the risks and benefits of VBAC versus elective repeat cesarean, a management plan was made and documented.
The patient underwent an uncomplicated cesarean section at 39 weeks and delivered a healthy baby.
VBAC is not an option where facilities fall short
Despite meeting VBAC criteria for previous incision or pelvic adequacy, many US women do not have the option of a trial of labor. The reason: the need for obstetric care providers throughout active labor and the ability to perform an emergency cesarean.1 As a result, many midwives and family practitioners can no longer care for VBAC patients independently.
Continuous monitoring is a must
It is the potential for uterine rupture that places patients at risk for unfavorable obstetric outcomes—and rupture can be hard to predict. A nonreassuring fetal heart rate is the most frequent sign.1 Others are uterine or abdominal pain, vaginal bleeding, loss of station of the presenting part, and hypovolemia.1
Continuous electronic monitoring of the fetal heart has the potential to detect nonreassuring events earlier than intermittent auscultation. Thus, continuous fetal heart rate monitoring has become the standard for women attempting VBAC. When it is unavailable, VBAC should not be offered.
Also crucial: Anesthesiology
ACOG recommends that anesthesia and other personnel be on hand in case emergency cesarean is warranted.1 While teaching hospitals and large referral centers are constantly staffed with obstetricians and anesthesiologists, birthing centers and smaller community-based hospitals often lack such coverage. As a result, some physicians and hospitals have withdrawn VBAC as an option
Reducing medicolegal risk
When a trial of labor results in uterine rupture or other adverse outcomes, the patient is more likely to sue. Informed consent and thorough documentation of the VBAC decision are crucial and should include37:
- Appropriate discussion of maternal and perinatal risks and benefits, and documentation of this exchange.
- A clear statement of the woman’s intention to undergo a trial of labor after cesarean delivery.
- If possible, documentation of previous uterine scar on the prenatal record.
- Appropriate counseling about the increased risk of rupture when labor is induced with oxytocin, and documentation of this discussion.
- Counseling about the increased risk of rupture when a trial of labor follows a previous cesarean by less than 19 months.
- Discussion about decreased likelihood of success if the woman is obese, is of advanced age, or has not had a prior vaginal birth.
Is VBAC availability better for health and happiness?
Many women want the option of a trial of labor after cesarean because it affords them the opportunity to experience vaginal delivery. Women who have undergone both cesarean and vaginal deliveries usually opt for a trial of labor in their next pregnancy.38 When a physician or hospital eliminates VBAC as an option, it can lead to patient dissatisfaction—as well as loss of revenue if a woman seeks care elsewhere.
Risk of placenta accreta
If elective repeat cesarean were the only option, the incidence of placenta accreta would increase over time.
Placenta accreta is strongly linked to placenta previa, a condition recognized to increase as the number of previous cesarean sections rises.39,40 A woman with 2 prior cesareans has a 2% incidence of placenta previa; nearly half of these cases are associated with placenta accreta.41 As a result, complications of accreta such as maternal death, need for substantial transfusion, postoperative infection, and intraoperative urinary tract injuries would be expected to increase if VBAC were abandoned.42
For this reason, it is important to ask about the patient’s childbearing goals. If a large family is planned, the potential risk of placenta accreta should be explained.
Assess for accreta. All patients with a prior cesarean section require careful evaluation of placental location and assessment for possible accreta should placenta previa or a low-lying placenta be identified prenatally.
I have found both ultrasound and magnetic resonance imaging useful in recognizing accreta, allowing for adequate preoperative preparation and more favorable outcomes. If accreta is not detected until the time of elective repeat cesarean, it can be life-threatening for the patient.
Should we abandon VBAC?
An unfortunate result of the initiatives promoting VBAC in the 1980s and 90s was a higher rate of uterine rupture, since many women with previous cesarean were strongly encouraged—even required—to undergo a trial of labor. Now that elective repeat cesareans are again on the rise, the risk of rupture should diminish due to better VBAC patient selection, but will probably remain substantially higher than for repeat cesarean.
What exactly is the risk of rupture?
In 1 population-based, retrospective cohort analysis25 involving 20,095 women with 1 previous cesarean section, researchers found a rate of uterine rupture of 5.2 per 1,000 women when labor was spontaneous, compared with 1.6 per 1,000 women who underwent elective repeat cesarean without labor. For women having labor induced with prostaglandins or by other means, the rates were 24.5 and 7.7 per 1,000, respectively.
In the same study, the relative risk of uterine rupture was 3.3 for women presenting in spontaneous labor, compared with those who underwent repeat cesarean without labor; it was 15.6 and 4.9 for women whose labor was induced with prostaglandins or by other means, respectively. The rate of infant mortality was 5.5% in cases involving uterine rupture, compared with 0.5% without rupture.25
Note that this study covered the years 1987 through 1996—and thus predated ACOG rules requiring round-the-clock obstetric and anesthesia care, and those barring prostaglandins for labor induction.
Perinatal death more likely with VBAC, but absolute risk is low
A separate population-based, retrospective, cohort study18 focused on different outcomes: intrapartum stillbirth or neonatal death. This study involved 313,238 singleton births at 37 to 43 weeks’ gestation with the fetus in a cephalic presentation.
Among the women opting for VBAC, the overall rate of delivery-related perinatal death was 12.9 per 10,000 women. This was approximately 11 times greater than the risk associated with planned repeat cesarean, more than twice the risk associated with labor in multiparous women, and similar to the risk among nulliparous women in labor. However, in absolute terms, the risk of perinatal death associated with a trial of labor and uterine rupture was low: 1 in 2,200.18
What’s the bottom line?
Are findings such as these reason to abandon VBAC? Not necessarily. VBAC success rates range from 60% to 80%, and a 1991 meta-analysis43 of more than 30 US studies found lower maternal febrile morbidity after a trial of labor than after repeat cesarean, and no differences between the 2 approaches in uterine dehiscence, rupture, or perinatal mortality.
A more recent meta-analysis9 of international studies involving 47,682 women found a uterine rupture rate of 0.4% for women undergoing a trial of labor versus 0.2% for those having elective repeat cesarean. A later meta-analysis, also international, found an overall uterine rupture rate of 6.2 per 1,000 women attempting VBAC, with a perinatal mortality rate of 0.4 per 1,000. Perinatal mortality was significantly lower among US studies.6
Nevertheless, when it comes to VBAC, absolute risks are low, and planned repeat cesarean does not eliminate them entirely. Elective cesarean carries a risk of maternal death up to 2.8 times that of vaginal delivery, though absolute risk is low.44
Thus, when patients are carefully selected and fully informed of benefits and risks, VBAC should remain an available option.
The author reports no relevant financial relationships.
1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin #54: Vaginal Birth After Previous Cesarean Delivery. Washington, DC: ACOG; July 2004.
2. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep. 2003;52(10):1-113.
3. Rageth JC, Juzi C, Grossenbacher H. for the Swiss Working Group of Obstetric and Gynecologic Institutions. Delivery after previous cesarean: a risk evaluation. Obstet Gynecol. 1999;93:332-337.
4. Hibbard JU, Ismail MA, Wang Y, Te C, Karrison T, Ismail MA. Failed vaginal birth after a cesarean section: how risky is it? I. Maternal morbidity. Am J Obstet Gynecol. 2001;184:1365-1371;discussion 1371–1373.
5. Bujold E, Gauthier RJ. Should we allow a trial of labor after a previous cesarean for dystocia in the second stage of labor? Obstet Gynecol. 2001;98:652-655.
6. Chauhan SP, Martin JN, Jr, Henrichs CE, Morrison JC, Magann EF. Maternal and perinatal complications with uterine rupture in 142,075 patients who attempted vaginal birth after cesarean delivery: a review of the literature. Am J Obstet Gynecol. 2003;189:408-417.
7. Gregory KD, Korst LM, Cane P, Platt LD, Kahn K. Vaginal birth after cesarean and uterine rupture rates in California. Obstet Gynecol. 1999;94:985-989.
8. Kieser KE, Baskett TF. A 10-year population-based study of uterine rupture. Obstet Gynecol. 2002;100:749-753.
9. Mozurkewich EL, Hutton EK. Elective repeat cesarean delivery versus trial of labor: a meta-analysis of the literature from 1989 to 1999. Am J Obstet Gynecol. 2000;183:1187-1197.
10. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Outcomes of a trial of labor following previous cesarean delivery among women with fetuses weighing >4,000 g. Am J Obstet Gynecol. 2001;185:903-905.
11. Zelop CM, Shipp TD, Cohen A, Repke JT, Lieberman E. Trial of labor after 40 weeks’ gestation in women with prior cesarean. Obstet Gynecol. 2001;97:391-393.
12. Macones GA, Hausman N, Edelstein R, Stamilio DM, Marder SJ. Predicting outcomes of trials of labor in women attempting vaginal birth after cesarean delivery: a comparison of multivariate methods with neural networks. Am J Obstet Gynecol. 2001;184:409-413.
13. Ravasia DJ, Wood SL, Pollard JK. Uterine rupture during induced trial of labor among women with previous cesarean delivery. Am J Obstet Gynecol. 2000;183:1176-1179.
14. Sims EJ, Newman RB, Hulsey TC. Vaginal birth after cesarean: to induce or not to induce. Am J Obstet Gynecol. 2001;184:1122-1124.
15. Chauhan SP, Magann EF, Carroll CS, Barrilleaux PS, Scardo JA, Marttin JN, Jr. Mode of delivery for the morbidly obese with prior cesarean delivery: vaginal versus repeat cesarean section. Am J Obstet Gynecol. 2001;185:349-354.
16. Carroll CS, Sr, Magann EF, Chauhan SP, Klauser CK, Morrison JC. Vaginal birth after cesarean section versus elective repeat cesarean delivery: weight-based outcomes. Am J Obstet Gynecol. 2003;188:1516-1520;discussion 1520–1522.
17. Huang WH, Nakashima DK, Rumney PJ, Keegan KA, Jr, Chan K. Interdelivery interval and the success of vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:41-44.
18. Smith GC, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA. 2002;287:2684-2690.
19. Bretelle F, Cravello L, Shojai R, Roger V, D’Ercole C, Blanc B. Vaginal birth following two previous cesarean sections. Eur J Obstet Gynecol Reprod Biol. 2001;94:23-26.
20. Shipp TD, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Intrapartum uterine rupture and dehiscence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol. 1999;94:735-740.
21. Naef RW, Ray MA, Chauhan SP, Roach H, Blake PG, Martin JN. Trial of labor after cesarean delivery with a lower-segment, vertical uterine incision: is it safe? Am J Obstet Gynecol. 1995;172:1666-1673.
22. Bujold E, Mehta SH, Bujold C, Gauthier RJ. Interdelivery interval and uterine rupture. Am J Obstet Gynecol. 2002;187:1199-1202.
23. Shipp TD, Zelop CM, Repke JT, Cohen A, Lieberman E. Interdelivery interval and risk of symptomatic uterine rupture. Obstet Gynecol. 2001;97:175-177.
24. Esposito MA, Menihan CA, Malee MP. Association of interpregnancy interval with uterine scar failure in labor: a case control study. Am J Obstet Gynecol. 2000;183:1180-1183.
25. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med. 2001;345:3-8.
26. American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. Committee Opinion: Induction of labor for vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:679-680.
27. Elkousy MA, Sammel M, Stevens E, Peipert JF, Macones G. The effect of birth weight on vaginal birth after cesarean delivery success rates. Am J Obstet Gynecol. 2003;188:824-830.
28. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Effects of previous vaginal delivery on the risk of uterine rupture during a subsequent trial of labor. Am J Obstet Gynecol. 2000;183:1184-1186.
29. Flamm BL, Fried MW, Lonky NM, Giles WS. External cephalic version after previous cesarean section. Am J Obstet Gynecol. 1991;165:370-372.
30. Myles T. Vaginal birth of twins after a previous cesarean section. J Matern Fetal Med. 2001;10:171-174.
31. Sansregret A, Bujold E, Gauthier RJ. Twin delivery after a previous cesarean: a 12-year experience. J Obstet Gynaecol Can. 2003;25:294-298.
32. Johnson C, Oriol N. The role of epidural anesthesia in trial of labor. Reg Anesth. 1990;15:304-308.
33. Sakala EP, Kaye S, Murray RD, Munson LJ. Epidural analgesia. Effect on the likelihood of a successful trial of labor after cesarean section. J Reprod Med. 1990;35:886-890.
34. Flamm BL. Once a cesarean, always a controversy. Obstet Gynecol. 1997;90:312-315.
35. McNally OM, Turner MJ. Induction of labor after 1 previous caesarean section. Aust N Z J Obstet Gynaecol. 1999;39:425-429.
36. Mankuta DD, Leshno MM, Menasche MM, Brezis MM. Vaginal birth after cesarean section: trial of labor or repeat cesarean section? A decision analysis. Am J Obstet Gynecol. 2003;189:714-719.
37. Martel MJ, MacKinnon CJ. Clinical Practice Obstetrics Committee of the Society of Obstetricians and Gynaecologists of Canada. Guidelines for vaginal birth after previous Caesarean birth. J Obstet Gynaecol Can. 2004;26:660-683.
38. McMahon MJ, Luther ER, Bowes WA, Olshan AF. Comparison of a trial of labor with an elective second section. N Engl J Med. 1996;335:689-695.
39. Ananth CV, Smulian JC, Vintzileos AM. The association of placenta previa with history of cesarean delivery and abortion: a metaanalysis. Am J Obstet Gynecol. 1997;177:1071-1078.
40. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa-placenta accreta. Am J Obstet Gynecol. 1997;177:210-214.
41. Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarean section. Obstet Gynecol. 1985;66:89-92.
42. O’Brien JM, Barton JR, Donaldson ES. The management of placenta percreta: conservative and operative strategies. Am J Obstet Gynecol. 1996;175:1632-1638.
43. Rosen MG, Dickinson JC, Westhoff CL. Vaginal birth after cesarean: a meta-analysis of morbidity and mortality. Obstet Gynecol. 1991;77:465-470.
44. Hall MH, Bewley S. Maternal mortality and mode of delivery. Lancet. 1999;354:776.-
1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin #54: Vaginal Birth After Previous Cesarean Delivery. Washington, DC: ACOG; July 2004.
2. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep. 2003;52(10):1-113.
3. Rageth JC, Juzi C, Grossenbacher H. for the Swiss Working Group of Obstetric and Gynecologic Institutions. Delivery after previous cesarean: a risk evaluation. Obstet Gynecol. 1999;93:332-337.
4. Hibbard JU, Ismail MA, Wang Y, Te C, Karrison T, Ismail MA. Failed vaginal birth after a cesarean section: how risky is it? I. Maternal morbidity. Am J Obstet Gynecol. 2001;184:1365-1371;discussion 1371–1373.
5. Bujold E, Gauthier RJ. Should we allow a trial of labor after a previous cesarean for dystocia in the second stage of labor? Obstet Gynecol. 2001;98:652-655.
6. Chauhan SP, Martin JN, Jr, Henrichs CE, Morrison JC, Magann EF. Maternal and perinatal complications with uterine rupture in 142,075 patients who attempted vaginal birth after cesarean delivery: a review of the literature. Am J Obstet Gynecol. 2003;189:408-417.
7. Gregory KD, Korst LM, Cane P, Platt LD, Kahn K. Vaginal birth after cesarean and uterine rupture rates in California. Obstet Gynecol. 1999;94:985-989.
8. Kieser KE, Baskett TF. A 10-year population-based study of uterine rupture. Obstet Gynecol. 2002;100:749-753.
9. Mozurkewich EL, Hutton EK. Elective repeat cesarean delivery versus trial of labor: a meta-analysis of the literature from 1989 to 1999. Am J Obstet Gynecol. 2000;183:1187-1197.
10. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Outcomes of a trial of labor following previous cesarean delivery among women with fetuses weighing >4,000 g. Am J Obstet Gynecol. 2001;185:903-905.
11. Zelop CM, Shipp TD, Cohen A, Repke JT, Lieberman E. Trial of labor after 40 weeks’ gestation in women with prior cesarean. Obstet Gynecol. 2001;97:391-393.
12. Macones GA, Hausman N, Edelstein R, Stamilio DM, Marder SJ. Predicting outcomes of trials of labor in women attempting vaginal birth after cesarean delivery: a comparison of multivariate methods with neural networks. Am J Obstet Gynecol. 2001;184:409-413.
13. Ravasia DJ, Wood SL, Pollard JK. Uterine rupture during induced trial of labor among women with previous cesarean delivery. Am J Obstet Gynecol. 2000;183:1176-1179.
14. Sims EJ, Newman RB, Hulsey TC. Vaginal birth after cesarean: to induce or not to induce. Am J Obstet Gynecol. 2001;184:1122-1124.
15. Chauhan SP, Magann EF, Carroll CS, Barrilleaux PS, Scardo JA, Marttin JN, Jr. Mode of delivery for the morbidly obese with prior cesarean delivery: vaginal versus repeat cesarean section. Am J Obstet Gynecol. 2001;185:349-354.
16. Carroll CS, Sr, Magann EF, Chauhan SP, Klauser CK, Morrison JC. Vaginal birth after cesarean section versus elective repeat cesarean delivery: weight-based outcomes. Am J Obstet Gynecol. 2003;188:1516-1520;discussion 1520–1522.
17. Huang WH, Nakashima DK, Rumney PJ, Keegan KA, Jr, Chan K. Interdelivery interval and the success of vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:41-44.
18. Smith GC, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA. 2002;287:2684-2690.
19. Bretelle F, Cravello L, Shojai R, Roger V, D’Ercole C, Blanc B. Vaginal birth following two previous cesarean sections. Eur J Obstet Gynecol Reprod Biol. 2001;94:23-26.
20. Shipp TD, Zelop CM, Repke JT, Cohen A, Caughey AB, Lieberman E. Intrapartum uterine rupture and dehiscence in patients with prior lower uterine segment vertical and transverse incisions. Obstet Gynecol. 1999;94:735-740.
21. Naef RW, Ray MA, Chauhan SP, Roach H, Blake PG, Martin JN. Trial of labor after cesarean delivery with a lower-segment, vertical uterine incision: is it safe? Am J Obstet Gynecol. 1995;172:1666-1673.
22. Bujold E, Mehta SH, Bujold C, Gauthier RJ. Interdelivery interval and uterine rupture. Am J Obstet Gynecol. 2002;187:1199-1202.
23. Shipp TD, Zelop CM, Repke JT, Cohen A, Lieberman E. Interdelivery interval and risk of symptomatic uterine rupture. Obstet Gynecol. 2001;97:175-177.
24. Esposito MA, Menihan CA, Malee MP. Association of interpregnancy interval with uterine scar failure in labor: a case control study. Am J Obstet Gynecol. 2000;183:1180-1183.
25. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med. 2001;345:3-8.
26. American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. Committee Opinion: Induction of labor for vaginal birth after cesarean delivery. Obstet Gynecol. 2002;99:679-680.
27. Elkousy MA, Sammel M, Stevens E, Peipert JF, Macones G. The effect of birth weight on vaginal birth after cesarean delivery success rates. Am J Obstet Gynecol. 2003;188:824-830.
28. Zelop CM, Shipp TD, Repke JT, Cohen A, Lieberman E. Effects of previous vaginal delivery on the risk of uterine rupture during a subsequent trial of labor. Am J Obstet Gynecol. 2000;183:1184-1186.
29. Flamm BL, Fried MW, Lonky NM, Giles WS. External cephalic version after previous cesarean section. Am J Obstet Gynecol. 1991;165:370-372.
30. Myles T. Vaginal birth of twins after a previous cesarean section. J Matern Fetal Med. 2001;10:171-174.
31. Sansregret A, Bujold E, Gauthier RJ. Twin delivery after a previous cesarean: a 12-year experience. J Obstet Gynaecol Can. 2003;25:294-298.
32. Johnson C, Oriol N. The role of epidural anesthesia in trial of labor. Reg Anesth. 1990;15:304-308.
33. Sakala EP, Kaye S, Murray RD, Munson LJ. Epidural analgesia. Effect on the likelihood of a successful trial of labor after cesarean section. J Reprod Med. 1990;35:886-890.
34. Flamm BL. Once a cesarean, always a controversy. Obstet Gynecol. 1997;90:312-315.
35. McNally OM, Turner MJ. Induction of labor after 1 previous caesarean section. Aust N Z J Obstet Gynaecol. 1999;39:425-429.
36. Mankuta DD, Leshno MM, Menasche MM, Brezis MM. Vaginal birth after cesarean section: trial of labor or repeat cesarean section? A decision analysis. Am J Obstet Gynecol. 2003;189:714-719.
37. Martel MJ, MacKinnon CJ. Clinical Practice Obstetrics Committee of the Society of Obstetricians and Gynaecologists of Canada. Guidelines for vaginal birth after previous Caesarean birth. J Obstet Gynaecol Can. 2004;26:660-683.
38. McMahon MJ, Luther ER, Bowes WA, Olshan AF. Comparison of a trial of labor with an elective second section. N Engl J Med. 1996;335:689-695.
39. Ananth CV, Smulian JC, Vintzileos AM. The association of placenta previa with history of cesarean delivery and abortion: a metaanalysis. Am J Obstet Gynecol. 1997;177:1071-1078.
40. Miller DA, Chollet JA, Goodwin TM. Clinical risk factors for placenta previa-placenta accreta. Am J Obstet Gynecol. 1997;177:210-214.
41. Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarean section. Obstet Gynecol. 1985;66:89-92.
42. O’Brien JM, Barton JR, Donaldson ES. The management of placenta percreta: conservative and operative strategies. Am J Obstet Gynecol. 1996;175:1632-1638.
43. Rosen MG, Dickinson JC, Westhoff CL. Vaginal birth after cesarean: a meta-analysis of morbidity and mortality. Obstet Gynecol. 1991;77:465-470.
44. Hall MH, Bewley S. Maternal mortality and mode of delivery. Lancet. 1999;354:776.-