Clinical Review

It has long been recognized that setting realistic and achievable short-term goals can help people improve their health long-term. But does goal setting work for older adults with multiple health issues or cognitive impairment? Researchers from the University of Pittsburgh in Pennsylvania conducted a study to find out.

They asked 27 patients from the University of Pittsburgh Medical Center Benedum Geriatric Center, a multidisciplinary outpatient geriatric clinic, to use goal attainment scaling (GAS) to set 2 to 4 activity-based goals to work toward. Goal attainment scaling is a tool for setting quantifiable patient-centered goals, measuring improvement toward the goals, and facilitating communication of shared priorities between patient and provider, the researchers say. They note that although originally designed for use in mental health, GAS has been used effectively as an outcome measure with older adults in multiple settings.

Related: Infusing Gerontologic Practice Into PACT

In a guided hour-by-hour review of their typical day, patients were directed to choose activities from 3 major domains: self-care, productivity, and leisure. Using the GAS 5-point scale, the physicians helped patients specify goals and determine the criteria for attaining them. Physicians were asked to rate on a 5-point scale whether their patients’ goals were realistic. The physicians felt that 100% of the goals were realistic, and 93% of the goals were achievable.

The researchers also measured cognitive function, physical function, and disability. About half the patients had ≥ 10 medical diagnoses, and most had both medical and psychiatric diagnoses. Fourteen patients reported some form of caregiver support. Fifteen were evaluated as having cognitive impairment.

Related: Development and Evaluation of a Geriatric Mood Management Program

At baseline, 25 participants demonstrated the ability to set a minimum of 2 goals. One patient chose not to, and another, who had dementia, could not. In all, the participants set 60 goals, half of them addressing leisure activity, such as getting exercise, playing cards, and attending church. Thirty percent of goals reflected patients’ desires to improve their personal care, for example, improving functional mobility. The final 20% of goals addressed productivity, such as managing a budget and finances.

At the 8-week follow-up, patients evaluated their current performance of the goal activities in relation to the indicators for levels of goal attainment they had established at baseline. They were also asked to rate their satisfaction with the process on a 5-point scale.

At the follow-up, 21 participants reported gains in ≥ 1 of their goal areas, reflected in significant changes in their GAS scores (P < .001). The patients were also highly satisfied with the process and their progress. Interesting, and a bit surprising, the patients who had no caregiver support were more likely to achieve their goals.

Related: Mobility in the Elderly: Speed Counts Most

The researchers note that because they did not include any additional intervention beyond goal setting, their findings support existing research that suggests the process of personal goal setting is a strategy in and of itself for increasing motivation toward achieving goals.

Primary care has become the preferred setting for chronic disease management, the researchers say. A patient-centered model could help solve the “impending crisis” of a growing population with many chronic conditions. They suggest that using GAS might be a way to enhance patient engagement, motivation, and satisfaction; improve provider-patient communication; and foster collaborative or shared priorities between patients and health care providers.

Source
Toto PE, Skidmore ER, Terhorst L, Rosen J, Weiner DK. Arch Gerontol Geriatr. 2015;60(1):16-21.
doi: 10.1016/j.archger.2014.10.022.

It has long been recognized that setting realistic and achievable short-term goals can help people improve their health long-term. But does goal setting work for older adults with multiple health issues or cognitive impairment? Researchers from the University of Pittsburgh in Pennsylvania conducted a study to find out.

They asked 27 patients from the University of Pittsburgh Medical Center Benedum Geriatric Center, a multidisciplinary outpatient geriatric clinic, to use goal attainment scaling (GAS) to set 2 to 4 activity-based goals to work toward. Goal attainment scaling is a tool for setting quantifiable patient-centered goals, measuring improvement toward the goals, and facilitating communication of shared priorities between patient and provider, the researchers say. They note that although originally designed for use in mental health, GAS has been used effectively as an outcome measure with older adults in multiple settings.

Related: Infusing Gerontologic Practice Into PACT

In a guided hour-by-hour review of their typical day, patients were directed to choose activities from 3 major domains: self-care, productivity, and leisure. Using the GAS 5-point scale, the physicians helped patients specify goals and determine the criteria for attaining them. Physicians were asked to rate on a 5-point scale whether their patients’ goals were realistic. The physicians felt that 100% of the goals were realistic, and 93% of the goals were achievable.

The researchers also measured cognitive function, physical function, and disability. About half the patients had ≥ 10 medical diagnoses, and most had both medical and psychiatric diagnoses. Fourteen patients reported some form of caregiver support. Fifteen were evaluated as having cognitive impairment.

Related: Development and Evaluation of a Geriatric Mood Management Program

At baseline, 25 participants demonstrated the ability to set a minimum of 2 goals. One patient chose not to, and another, who had dementia, could not. In all, the participants set 60 goals, half of them addressing leisure activity, such as getting exercise, playing cards, and attending church. Thirty percent of goals reflected patients’ desires to improve their personal care, for example, improving functional mobility. The final 20% of goals addressed productivity, such as managing a budget and finances.

At the 8-week follow-up, patients evaluated their current performance of the goal activities in relation to the indicators for levels of goal attainment they had established at baseline. They were also asked to rate their satisfaction with the process on a 5-point scale.

At the follow-up, 21 participants reported gains in ≥ 1 of their goal areas, reflected in significant changes in their GAS scores (P < .001). The patients were also highly satisfied with the process and their progress. Interesting, and a bit surprising, the patients who had no caregiver support were more likely to achieve their goals.

Related: Mobility in the Elderly: Speed Counts Most

The researchers note that because they did not include any additional intervention beyond goal setting, their findings support existing research that suggests the process of personal goal setting is a strategy in and of itself for increasing motivation toward achieving goals.

Primary care has become the preferred setting for chronic disease management, the researchers say. A patient-centered model could help solve the “impending crisis” of a growing population with many chronic conditions. They suggest that using GAS might be a way to enhance patient engagement, motivation, and satisfaction; improve provider-patient communication; and foster collaborative or shared priorities between patients and health care providers.

Source
Toto PE, Skidmore ER, Terhorst L, Rosen J, Weiner DK. Arch Gerontol Geriatr. 2015;60(1):16-21.
doi: 10.1016/j.archger.2014.10.022.

It has long been recognized that setting realistic and achievable short-term goals can help people improve their health long-term. But does goal setting work for older adults with multiple health issues or cognitive impairment? Researchers from the University of Pittsburgh in Pennsylvania conducted a study to find out.

They asked 27 patients from the University of Pittsburgh Medical Center Benedum Geriatric Center, a multidisciplinary outpatient geriatric clinic, to use goal attainment scaling (GAS) to set 2 to 4 activity-based goals to work toward. Goal attainment scaling is a tool for setting quantifiable patient-centered goals, measuring improvement toward the goals, and facilitating communication of shared priorities between patient and provider, the researchers say. They note that although originally designed for use in mental health, GAS has been used effectively as an outcome measure with older adults in multiple settings.

Related: Infusing Gerontologic Practice Into PACT

In a guided hour-by-hour review of their typical day, patients were directed to choose activities from 3 major domains: self-care, productivity, and leisure. Using the GAS 5-point scale, the physicians helped patients specify goals and determine the criteria for attaining them. Physicians were asked to rate on a 5-point scale whether their patients’ goals were realistic. The physicians felt that 100% of the goals were realistic, and 93% of the goals were achievable.

The researchers also measured cognitive function, physical function, and disability. About half the patients had ≥ 10 medical diagnoses, and most had both medical and psychiatric diagnoses. Fourteen patients reported some form of caregiver support. Fifteen were evaluated as having cognitive impairment.

Related: Development and Evaluation of a Geriatric Mood Management Program

At baseline, 25 participants demonstrated the ability to set a minimum of 2 goals. One patient chose not to, and another, who had dementia, could not. In all, the participants set 60 goals, half of them addressing leisure activity, such as getting exercise, playing cards, and attending church. Thirty percent of goals reflected patients’ desires to improve their personal care, for example, improving functional mobility. The final 20% of goals addressed productivity, such as managing a budget and finances.

At the 8-week follow-up, patients evaluated their current performance of the goal activities in relation to the indicators for levels of goal attainment they had established at baseline. They were also asked to rate their satisfaction with the process on a 5-point scale.

At the follow-up, 21 participants reported gains in ≥ 1 of their goal areas, reflected in significant changes in their GAS scores (P < .001). The patients were also highly satisfied with the process and their progress. Interesting, and a bit surprising, the patients who had no caregiver support were more likely to achieve their goals.

Related: Mobility in the Elderly: Speed Counts Most

The researchers note that because they did not include any additional intervention beyond goal setting, their findings support existing research that suggests the process of personal goal setting is a strategy in and of itself for increasing motivation toward achieving goals.

Primary care has become the preferred setting for chronic disease management, the researchers say. A patient-centered model could help solve the “impending crisis” of a growing population with many chronic conditions. They suggest that using GAS might be a way to enhance patient engagement, motivation, and satisfaction; improve provider-patient communication; and foster collaborative or shared priorities between patients and health care providers.

Source
Toto PE, Skidmore ER, Terhorst L, Rosen J, Weiner DK. Arch Gerontol Geriatr. 2015;60(1):16-21.
doi: 10.1016/j.archger.2014.10.022.

In his book, Better: A Surgeon’s Notes on Performance, Atul Gawande asks the question, “What does it take to be good at something in which failure is so easy, so effortless?”¹ Consider this statement for just a moment. Every day, over 355,000 patents seek care in this nation’s EDs.² These visits have a wide-range of significance, from the low acuity and low impact self-limited problems to the cases in which every decision and every second counts. Reflect on the 1999 Institute of Medicine (IOM) report, “To Err is Human.” At that time, 16 years ago, this seminal work estimated that up to 98,000 people die each year (268 each day) as a result of errors made in US hospitals.³ Variability in documentation, for many reasons, is a plausible factor in underestimation of accurate numbers. Since 2001, the worrisome number of deaths reported by the IOM has been re-evaluated a number of times, with each successive “deep dive” looking more ominous than the last.

In 2013, John James published a more recent estimate of preventable adverse events in the Journal of Patient Safety.⁴ He applied a literature review method to target the Global Trigger Tool from the Institute for Healthcare Improvement as the litmus test to estimate preventable error. In this limited review, James found that between 210,000 and over 400,000 premature deaths per year (575-1,095 deaths per day) are associated with harm that is preventable in hospitals. This number accounts for approximately 17% of the annual US population mortality and exceeds the national death toll from chronic lower respiratory tract infections, strokes, and accidents.⁵ Estimates of serious harm events (ie, morbidity) appear to be significantly greater than mortality. The adoption of the electronic medical record has not eliminated inaccuracies due to variation in documentation, reluctance of providers to report known errors, and lack of patient perspective in the recounting of their medical stories. The enormous magnitude of public-health consequences due to medical errors thus seems clear.

We become doctors and nurses primarily to help people, and not to cause harm to anyone. When harm occurs as the result of medical errors, the gut-wrenching guilt and self-deprecation that follows for most of us, and the doubt cast on our abilities as physicians, raise the question of why errors happen, and why more is not done to prevent them or to mitigate the consequences.

An awareness of some of the circumstances that lead to error can be a tremendous help in its prevention. High reliability organizations recognize that humans are fallible and that variation in human factors contributes to error, while also focusing on building safer environments designed to create layers of defense against error and mitigate their impact. Blame, shame, and accusatory approaches fail to improve any type of error. Environmental and situational hazards such as ED overcrowding, understaffing, high-patient volumes, rigid throughput demands, lack of equipment/subspecialty services and support in the system are highly contributory and must be addressed. Systemic issues aside, there are compelling individual factors that can lead anyone to make a mistake. Although lessons learned from mistakes are paramount to improvement, an understanding and awareness of the science of error and the necessity of “mindful medicine” can help protect individuals from the personal tolls of making a mistake.

Cognitive Biases

There are five significant cognitive biases that can result in preventable errors: availability bias, anchoring bias, framing bias, confirmation bias, and premature closure. Availability bias favors the common diagnosis without proving its validity. Anchoring bias occurs when a prior diagnosis or opinion is favored and misleads one from the correct current diagnosis. Framing bias can occur when it is not recognized that the data fail to fit the diagnostic presumptions. Confirmation bias can result when information is selectively interpreted to confirm a belief. Premature closure can lead hastily to an incorrect, rushed diagnostic conclusion. The following case scenarios illustrate examples of each of these biases.

Case Scenario 1: The Most Common Diagnosis Versus Looking for the Needle in the Haystack

On a busy night in the ED, the fifth patient of an emergency physician’s (EP) fourth consecutive shift was a quiet young lady home from college during the flu season. With a temperature of 102.6˚F, a heart rate of 110 beats/minute, blood pressure of 105/68 mm Hg, respiratory rate of 16 breaths/minute, and an oxygen saturation of 100% on room air, the EP was confident she would see another case of influenza. With the patient’s body aches, fever, and cough, she clearly appeared to be suffering from the flu, just like so many others this particular week. After treating the patient with fluids, antipyretics, and reassurance, she was sent home to rest in her own bed, with care instructions for influenza.

Because influenza was prevalent in the community, and a myriad of patients with the virus were seen this particular week, the EP was assured that this young lady had the flu—until she returned the next day with a petechial rash and sepsis from bacterial meningitis. This case illustrates the influence of “availability bias” in decision making. Treating a myriad of patients with the same symptoms, some with positive influenza screens and others with negative screens, led the physician to believe that the correct diagnosis, influenza for this patient, was the most common, some might say logical, diagnosis, while discounting other, and more serious possibilities as improbable.

By referring to the disease process that comes to mind most easily, and basing a diagnosis on previous patient experiences with similar symptoms, availability bias confounded the ability to look deeper into other possible causes. A more thorough neck examination, and careful skin and neurological examinations, coupled with the knowledge of a negative rapid influenza test, might have provided enough information—or doubt—to change the physician’s frame of reference and initially establish the correct diagnosis.

“Availability Bias” Mitigating Strategy: Always take a moment to consider diagnoses other than the most common in the differential and prove why the common diagnosis is valid and why other diagnoses could not be the case. If unable to do so, go back and re-evaluate.

Case Scenario 2: It Is Not Always ‘What It Is’

The next patient, a woman in her late 20s, presented to the ED less than 48 hours after discharge from the trauma service at another hospital. She had been admitted after a motor vehicle accident that resulted in an isolated traumatic subarachnoid hemorrhage. After observation, with no surgical intervention, she was discharged in good condition and was able to resume her normal activities with supportive care for a persistent headache postinjury. However, the patient returned after 2 days to an ED closer to her home, because she felt “foggy” and more irritable than usual.

As is customary, this busy unit employs nursing preemptive (ie, standing) orders, and the patient was triaged and laboratory tests were drawn including a basic chemistry panel. Upon evaluation by the attending EP, a concern for re-bleed led to a request for a noncontrast computed tomography (CT) scan of the head, which was interpreted as stable with no new bleed. The case was discussed with the trauma service from the initial hospital and follow-up was arranged.

Prior to the follow-up appointment, the patient returned to the ED because of a further deterioration in mental status. A third head CT was taken and interpreted as stable; however, her serum sodium level was 114 mmol/L. This patient suffered from posttraumatic syndrome of inappropriate antidiuretic hormone secretion (SIADH), and a retrospective review of the laboratory values from the prior ED visit showed the sodium level to be abnormally low at 121 mmol/L.

This case is a good illustration of “anchoring bias,” in which the existing diagnosis of traumatic subarachnoid hemorrhage was maintained as the etiology of the patient’s symptoms, despite a new piece of significant information (ie, the low sodium level) that was not integrated into the differential of possible etiologies for continued deterioration of mental status. 

“Anchoring Bias” Mitigating Strategy: Awareness of the power of a prior diagnosis or opinion to mislead is paramount; be sure to carefully review all available data and account for anything that does not lie within the range expected for your diagnosis whenever a patient returns to the ED. 

Case Scenario 3: The Search for the Right Piece of the Puzzle

A merchant marine in his mid-40s had fever, jaundice, vomiting, and right upper-quadrant pain for 2 days. He had been airlifted off his ship in the mid-Atlantic Ocean because the medical crew on the ship was concerned that he had a life-threatening illness and they had no surgical facilities available to care for acute cholecystitis with ascending cholangitis.

This patient was otherwise healthy and had all current immunizations. Upon arrival in the ED, he was given intravenous (IV) fluids, antiemetics, and medication for pain control while the workup was underway. He was somnolent and critically ill-appearing. As he spoke only German, a Red Cross interpreter was engaged in an attempt to obtain further information, but the patient was unable to provide additional history. The physician was able to elicit the travel history of the ship by connecting the interpreter with a crewmember on board and learned that the ship was on a return voyage from Haiti, a country endemic with Plasmodium falciparum. It was further determined that this patient was not taking malaria prophylaxis; his blood smear turned out to be positive for the disease.

This case emphasizes the impact of “framing bias” in the thought process that led to the initial diagnosis of ascending cholangitis. Charcot’s Triad of fever, jaundice, and right upper-quadrant pain was the “frame” in which the suspected—yet uncommon—diagnosis was made. The frame of reference, however, changed significantly when the additional information of P. falciparum malaria exposure was elucidated, allowing the correct diagnosis to come into view.

I “Framing Bias” Mitigation Strategy: Confirm that the points of data align properly and fit within the diagnostic possibilities. If they do not connect, seek further information and widen the frame of reference.

Case Scenario 4: Mother Knows Best

The parents of an 11-year-old boy brought their child to the ED for abdominal pain, nausea, and vomiting that started 10 hours prior to presentation. The boy had no medical or surgical history. During the examination, his mother expressed concern for appendicitis, a common concern of parents whose children have abdominal pain.

Although the boy was uncomfortable, he had no right lower-quadrant tenderness; his bowel sounds were normal, and there was no tenderness to heel tap or Rovsing’s sign. He did have periumbilical tenderness and distractible guarding. His white blood-cell (WBC) count was 12.5 K/uL with 78% segmented neutrophils and urinalysis showed 15 WBCs/hpf with no bacteria. With IV hydration, opioid pain medication, and antiemetic medication, the patient felt much better, and the abdominal examination improved with no tenderness.

After a clear liquid trial was successful, careful counseling of the parents made it clear that appendicitis was possible, but unlikely given the improvement in symptoms, and the boy was discharged with the diagnosis of acute gastroenteritis. Six hours later, the boy was brought back to the ED and then taken to the operating room for acute appendicitis.

This case illustrates the effect of “confirmation bias,” in which the preference to favor a particular diagnosis outweighs the clinical clues that suggested the correct diagnosis. Neither possible opioid effect in masking pain nor the lack of history or complaint of diarrhea was effectively taken into consideration before making the diagnosis of “gastroenteritis.”

I “Confirmation Bias” Mitigating Strategy: Be aware that selective filtering of information to confirm a belief is wrought with danger. Seek data and information that could weaken or negate the belief and give it serious consideration.

Case Scenario 5: The “Frequent Flyer”

This case involved an extremely difficult-to-manage patient who had presented to the ED many times in the past with “the worst headache of his life.” During these visits, he was typically disruptive, problematic to discharge safely, and a particular behavioral issue for the nurses. As a result, when he presented to the ED, the goal was to evaluate him quickly, treat him humanely, and diagnose and discharge him as soon as possible. He was never accompanied by family or friends. His personal medical history was positive for uncontrolled hypertension and chronic alcoholism.

Attempts to coordinate his care with social services and community mental health were unsuccessful. On examination, his blood pressure was 210/105 mm Hg and a severe headache was once again his chief complaint. A head CT scan performed less than 12 hours prior to this presentation revealed no new findings compared with many prior CTs. However, there was a slight slurring of his speech on this visit that wasn’t part of his prior presentations. After he was given lorazepam and a meal tray, the patient felt a little better and was discharged. The patient never returned to the ED, and the staff has since become concerned that on this last ED visit, their “frequent flyer” had something real.

Although it is not known what exactly happened to this patient, the manner in which he was treated represents the effect of premature closure on the medical decision-making process. When a clinician jumps to conclusions without seeking more information, the possibility of an error in judgment exists.

I “Premature Closure” Mitigating Strategies: Never stop thinking even after a conclusion has been reached. Instead, stop and think again about what else could be happening.

Conclusion

In all of the case scenarios presented, any or all of the patients might have survived the errors made without any adverse outcome, but the errors might also have resulted in mild to severe permanent disability or death. It is important to remember that errors can happen regardless of good intentions and acceptable practice, and that although an error may have no consequence in one set of circumstances, the same error could be deadly in others.

On the systems level, approaches to assess and control the work environment are necessary to mitigate risk to individuals, create a culture of safety, and encourage collective learning and continuous improvement. Recognition of the frequent incidence of error and awareness of the overlapping cognitive biases (Table), while always being mindful to take a moment to think further, can help avoid—but never eliminate--these types of mistakes. 

Dr McCammon is an assistant professor, department of emergency medicine, Eastern Virginia Medical School, Norfolk.

In his book, Better: A Surgeon’s Notes on Performance, Atul Gawande asks the question, “What does it take to be good at something in which failure is so easy, so effortless?”¹ Consider this statement for just a moment. Every day, over 355,000 patents seek care in this nation’s EDs.² These visits have a wide-range of significance, from the low acuity and low impact self-limited problems to the cases in which every decision and every second counts. Reflect on the 1999 Institute of Medicine (IOM) report, “To Err is Human.” At that time, 16 years ago, this seminal work estimated that up to 98,000 people die each year (268 each day) as a result of errors made in US hospitals.³ Variability in documentation, for many reasons, is a plausible factor in underestimation of accurate numbers. Since 2001, the worrisome number of deaths reported by the IOM has been re-evaluated a number of times, with each successive “deep dive” looking more ominous than the last.

In 2013, John James published a more recent estimate of preventable adverse events in the Journal of Patient Safety.⁴ He applied a literature review method to target the Global Trigger Tool from the Institute for Healthcare Improvement as the litmus test to estimate preventable error. In this limited review, James found that between 210,000 and over 400,000 premature deaths per year (575-1,095 deaths per day) are associated with harm that is preventable in hospitals. This number accounts for approximately 17% of the annual US population mortality and exceeds the national death toll from chronic lower respiratory tract infections, strokes, and accidents.⁵ Estimates of serious harm events (ie, morbidity) appear to be significantly greater than mortality. The adoption of the electronic medical record has not eliminated inaccuracies due to variation in documentation, reluctance of providers to report known errors, and lack of patient perspective in the recounting of their medical stories. The enormous magnitude of public-health consequences due to medical errors thus seems clear.

We become doctors and nurses primarily to help people, and not to cause harm to anyone. When harm occurs as the result of medical errors, the gut-wrenching guilt and self-deprecation that follows for most of us, and the doubt cast on our abilities as physicians, raise the question of why errors happen, and why more is not done to prevent them or to mitigate the consequences.

An awareness of some of the circumstances that lead to error can be a tremendous help in its prevention. High reliability organizations recognize that humans are fallible and that variation in human factors contributes to error, while also focusing on building safer environments designed to create layers of defense against error and mitigate their impact. Blame, shame, and accusatory approaches fail to improve any type of error. Environmental and situational hazards such as ED overcrowding, understaffing, high-patient volumes, rigid throughput demands, lack of equipment/subspecialty services and support in the system are highly contributory and must be addressed. Systemic issues aside, there are compelling individual factors that can lead anyone to make a mistake. Although lessons learned from mistakes are paramount to improvement, an understanding and awareness of the science of error and the necessity of “mindful medicine” can help protect individuals from the personal tolls of making a mistake.

Cognitive Biases

There are five significant cognitive biases that can result in preventable errors: availability bias, anchoring bias, framing bias, confirmation bias, and premature closure. Availability bias favors the common diagnosis without proving its validity. Anchoring bias occurs when a prior diagnosis or opinion is favored and misleads one from the correct current diagnosis. Framing bias can occur when it is not recognized that the data fail to fit the diagnostic presumptions. Confirmation bias can result when information is selectively interpreted to confirm a belief. Premature closure can lead hastily to an incorrect, rushed diagnostic conclusion. The following case scenarios illustrate examples of each of these biases.

Case Scenario 1: The Most Common Diagnosis Versus Looking for the Needle in the Haystack

On a busy night in the ED, the fifth patient of an emergency physician’s (EP) fourth consecutive shift was a quiet young lady home from college during the flu season. With a temperature of 102.6˚F, a heart rate of 110 beats/minute, blood pressure of 105/68 mm Hg, respiratory rate of 16 breaths/minute, and an oxygen saturation of 100% on room air, the EP was confident she would see another case of influenza. With the patient’s body aches, fever, and cough, she clearly appeared to be suffering from the flu, just like so many others this particular week. After treating the patient with fluids, antipyretics, and reassurance, she was sent home to rest in her own bed, with care instructions for influenza.

Because influenza was prevalent in the community, and a myriad of patients with the virus were seen this particular week, the EP was assured that this young lady had the flu—until she returned the next day with a petechial rash and sepsis from bacterial meningitis. This case illustrates the influence of “availability bias” in decision making. Treating a myriad of patients with the same symptoms, some with positive influenza screens and others with negative screens, led the physician to believe that the correct diagnosis, influenza for this patient, was the most common, some might say logical, diagnosis, while discounting other, and more serious possibilities as improbable.

By referring to the disease process that comes to mind most easily, and basing a diagnosis on previous patient experiences with similar symptoms, availability bias confounded the ability to look deeper into other possible causes. A more thorough neck examination, and careful skin and neurological examinations, coupled with the knowledge of a negative rapid influenza test, might have provided enough information—or doubt—to change the physician’s frame of reference and initially establish the correct diagnosis.

“Availability Bias” Mitigating Strategy: Always take a moment to consider diagnoses other than the most common in the differential and prove why the common diagnosis is valid and why other diagnoses could not be the case. If unable to do so, go back and re-evaluate.

Case Scenario 2: It Is Not Always ‘What It Is’

The next patient, a woman in her late 20s, presented to the ED less than 48 hours after discharge from the trauma service at another hospital. She had been admitted after a motor vehicle accident that resulted in an isolated traumatic subarachnoid hemorrhage. After observation, with no surgical intervention, she was discharged in good condition and was able to resume her normal activities with supportive care for a persistent headache postinjury. However, the patient returned after 2 days to an ED closer to her home, because she felt “foggy” and more irritable than usual.

As is customary, this busy unit employs nursing preemptive (ie, standing) orders, and the patient was triaged and laboratory tests were drawn including a basic chemistry panel. Upon evaluation by the attending EP, a concern for re-bleed led to a request for a noncontrast computed tomography (CT) scan of the head, which was interpreted as stable with no new bleed. The case was discussed with the trauma service from the initial hospital and follow-up was arranged.

Prior to the follow-up appointment, the patient returned to the ED because of a further deterioration in mental status. A third head CT was taken and interpreted as stable; however, her serum sodium level was 114 mmol/L. This patient suffered from posttraumatic syndrome of inappropriate antidiuretic hormone secretion (SIADH), and a retrospective review of the laboratory values from the prior ED visit showed the sodium level to be abnormally low at 121 mmol/L.

This case is a good illustration of “anchoring bias,” in which the existing diagnosis of traumatic subarachnoid hemorrhage was maintained as the etiology of the patient’s symptoms, despite a new piece of significant information (ie, the low sodium level) that was not integrated into the differential of possible etiologies for continued deterioration of mental status. 

“Anchoring Bias” Mitigating Strategy: Awareness of the power of a prior diagnosis or opinion to mislead is paramount; be sure to carefully review all available data and account for anything that does not lie within the range expected for your diagnosis whenever a patient returns to the ED. 

Case Scenario 3: The Search for the Right Piece of the Puzzle

A merchant marine in his mid-40s had fever, jaundice, vomiting, and right upper-quadrant pain for 2 days. He had been airlifted off his ship in the mid-Atlantic Ocean because the medical crew on the ship was concerned that he had a life-threatening illness and they had no surgical facilities available to care for acute cholecystitis with ascending cholangitis.

This patient was otherwise healthy and had all current immunizations. Upon arrival in the ED, he was given intravenous (IV) fluids, antiemetics, and medication for pain control while the workup was underway. He was somnolent and critically ill-appearing. As he spoke only German, a Red Cross interpreter was engaged in an attempt to obtain further information, but the patient was unable to provide additional history. The physician was able to elicit the travel history of the ship by connecting the interpreter with a crewmember on board and learned that the ship was on a return voyage from Haiti, a country endemic with Plasmodium falciparum. It was further determined that this patient was not taking malaria prophylaxis; his blood smear turned out to be positive for the disease.

This case emphasizes the impact of “framing bias” in the thought process that led to the initial diagnosis of ascending cholangitis. Charcot’s Triad of fever, jaundice, and right upper-quadrant pain was the “frame” in which the suspected—yet uncommon—diagnosis was made. The frame of reference, however, changed significantly when the additional information of P. falciparum malaria exposure was elucidated, allowing the correct diagnosis to come into view.

I “Framing Bias” Mitigation Strategy: Confirm that the points of data align properly and fit within the diagnostic possibilities. If they do not connect, seek further information and widen the frame of reference.

Case Scenario 4: Mother Knows Best

The parents of an 11-year-old boy brought their child to the ED for abdominal pain, nausea, and vomiting that started 10 hours prior to presentation. The boy had no medical or surgical history. During the examination, his mother expressed concern for appendicitis, a common concern of parents whose children have abdominal pain.

Although the boy was uncomfortable, he had no right lower-quadrant tenderness; his bowel sounds were normal, and there was no tenderness to heel tap or Rovsing’s sign. He did have periumbilical tenderness and distractible guarding. His white blood-cell (WBC) count was 12.5 K/uL with 78% segmented neutrophils and urinalysis showed 15 WBCs/hpf with no bacteria. With IV hydration, opioid pain medication, and antiemetic medication, the patient felt much better, and the abdominal examination improved with no tenderness.

After a clear liquid trial was successful, careful counseling of the parents made it clear that appendicitis was possible, but unlikely given the improvement in symptoms, and the boy was discharged with the diagnosis of acute gastroenteritis. Six hours later, the boy was brought back to the ED and then taken to the operating room for acute appendicitis.

This case illustrates the effect of “confirmation bias,” in which the preference to favor a particular diagnosis outweighs the clinical clues that suggested the correct diagnosis. Neither possible opioid effect in masking pain nor the lack of history or complaint of diarrhea was effectively taken into consideration before making the diagnosis of “gastroenteritis.”

I “Confirmation Bias” Mitigating Strategy: Be aware that selective filtering of information to confirm a belief is wrought with danger. Seek data and information that could weaken or negate the belief and give it serious consideration.

Case Scenario 5: The “Frequent Flyer”

This case involved an extremely difficult-to-manage patient who had presented to the ED many times in the past with “the worst headache of his life.” During these visits, he was typically disruptive, problematic to discharge safely, and a particular behavioral issue for the nurses. As a result, when he presented to the ED, the goal was to evaluate him quickly, treat him humanely, and diagnose and discharge him as soon as possible. He was never accompanied by family or friends. His personal medical history was positive for uncontrolled hypertension and chronic alcoholism.

Attempts to coordinate his care with social services and community mental health were unsuccessful. On examination, his blood pressure was 210/105 mm Hg and a severe headache was once again his chief complaint. A head CT scan performed less than 12 hours prior to this presentation revealed no new findings compared with many prior CTs. However, there was a slight slurring of his speech on this visit that wasn’t part of his prior presentations. After he was given lorazepam and a meal tray, the patient felt a little better and was discharged. The patient never returned to the ED, and the staff has since become concerned that on this last ED visit, their “frequent flyer” had something real.

Although it is not known what exactly happened to this patient, the manner in which he was treated represents the effect of premature closure on the medical decision-making process. When a clinician jumps to conclusions without seeking more information, the possibility of an error in judgment exists.

I “Premature Closure” Mitigating Strategies: Never stop thinking even after a conclusion has been reached. Instead, stop and think again about what else could be happening.

Conclusion

In all of the case scenarios presented, any or all of the patients might have survived the errors made without any adverse outcome, but the errors might also have resulted in mild to severe permanent disability or death. It is important to remember that errors can happen regardless of good intentions and acceptable practice, and that although an error may have no consequence in one set of circumstances, the same error could be deadly in others.

On the systems level, approaches to assess and control the work environment are necessary to mitigate risk to individuals, create a culture of safety, and encourage collective learning and continuous improvement. Recognition of the frequent incidence of error and awareness of the overlapping cognitive biases (Table), while always being mindful to take a moment to think further, can help avoid—but never eliminate--these types of mistakes. 

Dr McCammon is an assistant professor, department of emergency medicine, Eastern Virginia Medical School, Norfolk.

In his book, Better: A Surgeon’s Notes on Performance, Atul Gawande asks the question, “What does it take to be good at something in which failure is so easy, so effortless?”¹ Consider this statement for just a moment. Every day, over 355,000 patents seek care in this nation’s EDs.² These visits have a wide-range of significance, from the low acuity and low impact self-limited problems to the cases in which every decision and every second counts. Reflect on the 1999 Institute of Medicine (IOM) report, “To Err is Human.” At that time, 16 years ago, this seminal work estimated that up to 98,000 people die each year (268 each day) as a result of errors made in US hospitals.³ Variability in documentation, for many reasons, is a plausible factor in underestimation of accurate numbers. Since 2001, the worrisome number of deaths reported by the IOM has been re-evaluated a number of times, with each successive “deep dive” looking more ominous than the last.

In 2013, John James published a more recent estimate of preventable adverse events in the Journal of Patient Safety.⁴ He applied a literature review method to target the Global Trigger Tool from the Institute for Healthcare Improvement as the litmus test to estimate preventable error. In this limited review, James found that between 210,000 and over 400,000 premature deaths per year (575-1,095 deaths per day) are associated with harm that is preventable in hospitals. This number accounts for approximately 17% of the annual US population mortality and exceeds the national death toll from chronic lower respiratory tract infections, strokes, and accidents.⁵ Estimates of serious harm events (ie, morbidity) appear to be significantly greater than mortality. The adoption of the electronic medical record has not eliminated inaccuracies due to variation in documentation, reluctance of providers to report known errors, and lack of patient perspective in the recounting of their medical stories. The enormous magnitude of public-health consequences due to medical errors thus seems clear.

We become doctors and nurses primarily to help people, and not to cause harm to anyone. When harm occurs as the result of medical errors, the gut-wrenching guilt and self-deprecation that follows for most of us, and the doubt cast on our abilities as physicians, raise the question of why errors happen, and why more is not done to prevent them or to mitigate the consequences.

An awareness of some of the circumstances that lead to error can be a tremendous help in its prevention. High reliability organizations recognize that humans are fallible and that variation in human factors contributes to error, while also focusing on building safer environments designed to create layers of defense against error and mitigate their impact. Blame, shame, and accusatory approaches fail to improve any type of error. Environmental and situational hazards such as ED overcrowding, understaffing, high-patient volumes, rigid throughput demands, lack of equipment/subspecialty services and support in the system are highly contributory and must be addressed. Systemic issues aside, there are compelling individual factors that can lead anyone to make a mistake. Although lessons learned from mistakes are paramount to improvement, an understanding and awareness of the science of error and the necessity of “mindful medicine” can help protect individuals from the personal tolls of making a mistake.

Cognitive Biases

There are five significant cognitive biases that can result in preventable errors: availability bias, anchoring bias, framing bias, confirmation bias, and premature closure. Availability bias favors the common diagnosis without proving its validity. Anchoring bias occurs when a prior diagnosis or opinion is favored and misleads one from the correct current diagnosis. Framing bias can occur when it is not recognized that the data fail to fit the diagnostic presumptions. Confirmation bias can result when information is selectively interpreted to confirm a belief. Premature closure can lead hastily to an incorrect, rushed diagnostic conclusion. The following case scenarios illustrate examples of each of these biases.

Case Scenario 1: The Most Common Diagnosis Versus Looking for the Needle in the Haystack

On a busy night in the ED, the fifth patient of an emergency physician’s (EP) fourth consecutive shift was a quiet young lady home from college during the flu season. With a temperature of 102.6˚F, a heart rate of 110 beats/minute, blood pressure of 105/68 mm Hg, respiratory rate of 16 breaths/minute, and an oxygen saturation of 100% on room air, the EP was confident she would see another case of influenza. With the patient’s body aches, fever, and cough, she clearly appeared to be suffering from the flu, just like so many others this particular week. After treating the patient with fluids, antipyretics, and reassurance, she was sent home to rest in her own bed, with care instructions for influenza.

Because influenza was prevalent in the community, and a myriad of patients with the virus were seen this particular week, the EP was assured that this young lady had the flu—until she returned the next day with a petechial rash and sepsis from bacterial meningitis. This case illustrates the influence of “availability bias” in decision making. Treating a myriad of patients with the same symptoms, some with positive influenza screens and others with negative screens, led the physician to believe that the correct diagnosis, influenza for this patient, was the most common, some might say logical, diagnosis, while discounting other, and more serious possibilities as improbable.

By referring to the disease process that comes to mind most easily, and basing a diagnosis on previous patient experiences with similar symptoms, availability bias confounded the ability to look deeper into other possible causes. A more thorough neck examination, and careful skin and neurological examinations, coupled with the knowledge of a negative rapid influenza test, might have provided enough information—or doubt—to change the physician’s frame of reference and initially establish the correct diagnosis.

“Availability Bias” Mitigating Strategy: Always take a moment to consider diagnoses other than the most common in the differential and prove why the common diagnosis is valid and why other diagnoses could not be the case. If unable to do so, go back and re-evaluate.

Case Scenario 2: It Is Not Always ‘What It Is’

The next patient, a woman in her late 20s, presented to the ED less than 48 hours after discharge from the trauma service at another hospital. She had been admitted after a motor vehicle accident that resulted in an isolated traumatic subarachnoid hemorrhage. After observation, with no surgical intervention, she was discharged in good condition and was able to resume her normal activities with supportive care for a persistent headache postinjury. However, the patient returned after 2 days to an ED closer to her home, because she felt “foggy” and more irritable than usual.

As is customary, this busy unit employs nursing preemptive (ie, standing) orders, and the patient was triaged and laboratory tests were drawn including a basic chemistry panel. Upon evaluation by the attending EP, a concern for re-bleed led to a request for a noncontrast computed tomography (CT) scan of the head, which was interpreted as stable with no new bleed. The case was discussed with the trauma service from the initial hospital and follow-up was arranged.

Prior to the follow-up appointment, the patient returned to the ED because of a further deterioration in mental status. A third head CT was taken and interpreted as stable; however, her serum sodium level was 114 mmol/L. This patient suffered from posttraumatic syndrome of inappropriate antidiuretic hormone secretion (SIADH), and a retrospective review of the laboratory values from the prior ED visit showed the sodium level to be abnormally low at 121 mmol/L.

This case is a good illustration of “anchoring bias,” in which the existing diagnosis of traumatic subarachnoid hemorrhage was maintained as the etiology of the patient’s symptoms, despite a new piece of significant information (ie, the low sodium level) that was not integrated into the differential of possible etiologies for continued deterioration of mental status. 

“Anchoring Bias” Mitigating Strategy: Awareness of the power of a prior diagnosis or opinion to mislead is paramount; be sure to carefully review all available data and account for anything that does not lie within the range expected for your diagnosis whenever a patient returns to the ED. 

Case Scenario 3: The Search for the Right Piece of the Puzzle

A merchant marine in his mid-40s had fever, jaundice, vomiting, and right upper-quadrant pain for 2 days. He had been airlifted off his ship in the mid-Atlantic Ocean because the medical crew on the ship was concerned that he had a life-threatening illness and they had no surgical facilities available to care for acute cholecystitis with ascending cholangitis.

This patient was otherwise healthy and had all current immunizations. Upon arrival in the ED, he was given intravenous (IV) fluids, antiemetics, and medication for pain control while the workup was underway. He was somnolent and critically ill-appearing. As he spoke only German, a Red Cross interpreter was engaged in an attempt to obtain further information, but the patient was unable to provide additional history. The physician was able to elicit the travel history of the ship by connecting the interpreter with a crewmember on board and learned that the ship was on a return voyage from Haiti, a country endemic with Plasmodium falciparum. It was further determined that this patient was not taking malaria prophylaxis; his blood smear turned out to be positive for the disease.

This case emphasizes the impact of “framing bias” in the thought process that led to the initial diagnosis of ascending cholangitis. Charcot’s Triad of fever, jaundice, and right upper-quadrant pain was the “frame” in which the suspected—yet uncommon—diagnosis was made. The frame of reference, however, changed significantly when the additional information of P. falciparum malaria exposure was elucidated, allowing the correct diagnosis to come into view.

I “Framing Bias” Mitigation Strategy: Confirm that the points of data align properly and fit within the diagnostic possibilities. If they do not connect, seek further information and widen the frame of reference.

Case Scenario 4: Mother Knows Best

The parents of an 11-year-old boy brought their child to the ED for abdominal pain, nausea, and vomiting that started 10 hours prior to presentation. The boy had no medical or surgical history. During the examination, his mother expressed concern for appendicitis, a common concern of parents whose children have abdominal pain.

Although the boy was uncomfortable, he had no right lower-quadrant tenderness; his bowel sounds were normal, and there was no tenderness to heel tap or Rovsing’s sign. He did have periumbilical tenderness and distractible guarding. His white blood-cell (WBC) count was 12.5 K/uL with 78% segmented neutrophils and urinalysis showed 15 WBCs/hpf with no bacteria. With IV hydration, opioid pain medication, and antiemetic medication, the patient felt much better, and the abdominal examination improved with no tenderness.

After a clear liquid trial was successful, careful counseling of the parents made it clear that appendicitis was possible, but unlikely given the improvement in symptoms, and the boy was discharged with the diagnosis of acute gastroenteritis. Six hours later, the boy was brought back to the ED and then taken to the operating room for acute appendicitis.

This case illustrates the effect of “confirmation bias,” in which the preference to favor a particular diagnosis outweighs the clinical clues that suggested the correct diagnosis. Neither possible opioid effect in masking pain nor the lack of history or complaint of diarrhea was effectively taken into consideration before making the diagnosis of “gastroenteritis.”

I “Confirmation Bias” Mitigating Strategy: Be aware that selective filtering of information to confirm a belief is wrought with danger. Seek data and information that could weaken or negate the belief and give it serious consideration.

Case Scenario 5: The “Frequent Flyer”

This case involved an extremely difficult-to-manage patient who had presented to the ED many times in the past with “the worst headache of his life.” During these visits, he was typically disruptive, problematic to discharge safely, and a particular behavioral issue for the nurses. As a result, when he presented to the ED, the goal was to evaluate him quickly, treat him humanely, and diagnose and discharge him as soon as possible. He was never accompanied by family or friends. His personal medical history was positive for uncontrolled hypertension and chronic alcoholism.

Attempts to coordinate his care with social services and community mental health were unsuccessful. On examination, his blood pressure was 210/105 mm Hg and a severe headache was once again his chief complaint. A head CT scan performed less than 12 hours prior to this presentation revealed no new findings compared with many prior CTs. However, there was a slight slurring of his speech on this visit that wasn’t part of his prior presentations. After he was given lorazepam and a meal tray, the patient felt a little better and was discharged. The patient never returned to the ED, and the staff has since become concerned that on this last ED visit, their “frequent flyer” had something real.

Although it is not known what exactly happened to this patient, the manner in which he was treated represents the effect of premature closure on the medical decision-making process. When a clinician jumps to conclusions without seeking more information, the possibility of an error in judgment exists.

I “Premature Closure” Mitigating Strategies: Never stop thinking even after a conclusion has been reached. Instead, stop and think again about what else could be happening.

Conclusion

In all of the case scenarios presented, any or all of the patients might have survived the errors made without any adverse outcome, but the errors might also have resulted in mild to severe permanent disability or death. It is important to remember that errors can happen regardless of good intentions and acceptable practice, and that although an error may have no consequence in one set of circumstances, the same error could be deadly in others.

On the systems level, approaches to assess and control the work environment are necessary to mitigate risk to individuals, create a culture of safety, and encourage collective learning and continuous improvement. Recognition of the frequent incidence of error and awareness of the overlapping cognitive biases (Table), while always being mindful to take a moment to think further, can help avoid—but never eliminate--these types of mistakes. 

Dr McCammon is an assistant professor, department of emergency medicine, Eastern Virginia Medical School, Norfolk.

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The first human birth from a frozen oocyte was reported in 1986.¹ Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.²

In this Update, we present the ­current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.

Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.

The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.³ Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.⁴

The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.

Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.⁵ The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.⁶

Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.⁵

In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.^7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.

Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of ­cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).⁹

Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.^9-11 A prospective randomized controlled trial ­comparing frozen/thawed with ­vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for ­vitrification/warming vs 67% for slow ­freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).¹⁰

The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.² The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.¹²

Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.

For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.¹³

Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.¹⁴ Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.¹⁵

In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 ­pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.¹⁶

We can freeze eggs, but when should we?
Based on media presentations and professional perspectives, it appears that many people differentiate between “medical” and “social” egg freezing.

Medical versus social freezing
Medical egg freezing is done when there is an immediate medical need to preserve fertility, such as before cancer treatment when the woman can’t reproduce now and will have reduced or no capacity later. Social freezing, on the other hand, occurs when there is no immediate need, such as when there is a desire to delay parenthood so that educational, professional, or other goals can be met. The difference is important because medical freezing is usually seen as a “need” and is therefore acceptable, whereas social freezing is elective or a “wish” and therefore is questionable.¹⁷

The labels are important for both ethical and political reasons because most people would consider medical freezing to be ethically acceptable and also worthy of societal support, perhaps even financial coverage, while some might consider social freezing to be neither ethically acceptable nor worthy of coverage.

What’s the difference?
But is the difference really all that clear? If a woman has a mother and a sister who have undergone premature menopause in their 30s and she now has signs of diminishing ovarian reserve in her late 20s, would a desire to freeze eggs be medical or social? She has no immediate need for treatment but a reasonable expectation of need later. One could argue that she should go to a sperm bank now if she has no partner, or change her life plans—but is this a reasonable expectation? If a woman is perfectly healthy but her husband has severe sperm problems and she elects IVF to treat male-factor infertility, is it medical or social? There are many situations in which it is unclear whether the reason for egg freezing would be medical or social.

Does it matter?
In any event, are social reasons to freeze eggs not legitimate? Many would argue that medical services should be used to treat diseases, not social causes. Yet we use medicine all the time to treat problems caused by social factors (obesity, depression, anxiety).

Some would argue that it is a personal decision to delay reproduction, and that health problems caused by personal decisions do not merit medical intervention. However, it is common to provide medical services to people who require the services only because of personal decisions—for instance, professional and amateur athletes who injure themselves pursuing activities for compensation or pleasure, or smokers or persons with alcoholism.

Others have argued that social freezing is inappropriate because it is only being done to avoid the consequences of aging, and that its need could be avoided by not waiting too long to get pregnant. But we treat many conditions that occur primarily as a result of aging (hypertension, dementia, poor eyesight).

Because it has become generally accepted to treat older women with diminished ovarian reserve and infertility, why is it inappropriate to treat women—when they are younger—with egg freezing to mitigate the impact of aging on reproductive performance that we know will occur later? If we could prevent or limit the impact of aging on the cardiovascular or neurologic systems by interventions earlier in a person’s life, would we not provide that medical service? Do we not provide statins and other medications to delay or limit the sequelae of aging? What is the difference with egg freezing?

Therefore, could it be discriminatory not to consider egg freezing ethical and acceptable, even if the reason for the procedure is considered social? Why should egg freezing for social reasons not be acceptable and widely available?

Who should pay for egg freezing?
Even if egg freezing performed because of social reasons is considered ethical and is supported by society, it does not necessarily follow that it will or should be paid for by society. The creation of policies determining coverage for health-care services is a complex process and is based on overall societal needs, economic capabilities, and relative social value of the services. Because infertility carries such a large personal burden and childbearing is so essential to any society, one can argue that infertility, per se, should be covered by society and, in the United States, its surrogate employers and insurance companies. This is often not the case, however. So, while it can be argued that egg freezing should be covered by insurance for both medical and social reasons, even the success of that argument does not mean it will be so in the current US health-care system.

Because egg freezing involves two major steps: (1) ovarian stimulation, egg retrieval, egg freezing, and egg storage followed at a later date by (2) egg thawing, fertilization, embryo culture, and embryo replacement in the uterus, what would be socially justified coverage of egg freezing? Society could cover just the first step or just the second, or both. Such decisions would depend on an assessment of the social benefit from coverage of these services. Such analysis is not yet available because of limited experience.

Is the cost worth it?
A major issue for women considering egg freezing for social reasons is whether a sufficient number of eggs will be retrieved to provide a reasonable chance for pregnancy later when they are used. The FIGURE illustrates the probability of a live birth after egg freezing. It should be noted that while most, but not all, eggs survive thawing after vitrification, not all eggs will become fertilized. Only about half of the fertilized eggs will grow to a day 3 embryo, and not all of those embryos will be viable. Therefore, constant reproductive loss occurs after the eggs are retrieved.
 

Source: Cil AP, et al.18 18

Furthermore, even after embryo replacement, pregnancy does not occur in every case, and some pregnancies are lost to miscarriage as well as other complications of pregnancy and childbirth. The FIGURE shows that a 25-year-old woman with 12 eggs frozen would have an estimated pregnancy rate much greater than 50%. However, the numbers also indicate that egg freezing is not very successful for older women who, at this time, constitute many of those considering the procedure.18

Another consideration is that a significant, but currently unknown, number of women who freeze their eggs will never use them for a variety of reasons. This is especially true of younger women, for whom many of the factors determining their eventual reproductive life might well change. They may eventually decide not to have children or they might become pregnant naturally or after fertility treatments that are cheaper than using the frozen eggs.

A $200,000 price tag?
Let’s consider the near 20% estimated pregnancy rate for age 35 in the FIGURE. If only half of the women aged 35 who freeze 6 eggs eventually use them (but, again, only about 20% have a baby), it means that only one of every 10 women who freeze their eggs eventually will have a baby as a result of the procedure. The number needed to treat (NNT) is therefore 10, and if the cost is $20,000 for the egg freezing procedure and storage over 5 to 10 years, the overall cost per baby born is about $200,000. If 12 eggs are frozen, the cost is $100,000. This clearly is a significant cost, and a greater cost than most other fertility treatments to achieve a baby, even in the older population. Therefore, the cost-effectiveness of social egg freezing is yet to be determined.

What should we do as we move forward?
Abandon the medical versus social rhetoric
It is difficult to argue against egg freezing for medical reasons, and the distinction between medical and social freezing is largely an artificial construct. In general, therefore, the differentiation between medical and social egg freezing should be abandoned, and egg freezing to preserve future fertility should be considered ethical for whatever reasons.

Consider the ideal time frame for health insurance coverage of egg freezing
That does not mean that egg freezing should always be reimbursed. The decision for coverage by employers, insurers, and other payers should be based on a cost–benefit analysis of the social benefit, individual benefit, biological chances of success, probability that the frozen eggs will be used, medical risks/sequelae, and the financial costs. Therefore, whether or not egg freezing for fertility preservation is covered will vary among countries and even within countries and among different individuals. Such an approach to coverage should apply to all medical interventions, including both medical and social egg freezing.

This approach could possibly result in findings and resulting policies that do not cover egg freezing before age 30 because too few women will return to use their eggs, or after age 38 because the chances of success are too low. Other instances of freezing should not be forbidden but would not be reimbursed by public or payer money.¹⁷

Many considerations must go into the development of social, professional, and payment policies. Policies that are seen as family-friendly that promote childbearing, especially at an earlier age, can be seen as limiting women’s academic and career opportunities and therefore women-unfriendly. Policies supporting women’s reproductive autonomy and ability to delay childbearing can be seen as women- but not family-friendly. Therefore, reproductive policies affect not only the individual woman but also society, its demographics, politics, and economics.¹⁷

The future
The new technology of egg freezing is a wonderful advance for many people. We are learning innovative ways to apply this technology for both infertile and noninfertile people. Research, better evidence, public education, informed consent, ethical practice of medicine, societal support for reproductive rights, and consideration of patient autonomy and social justice will enable us to optimize egg freezing as a treatment intervention.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

If Bob were your patient, how would you proceed? 

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the clinician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the clinician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

Next page: How common are PDs?

PDs ARE MORE COMMON THAN YOU MIGHT SUSPECT
The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (see Table 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually have several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

What to do if you suspect your patient has a PD >>

SUSPECT YOUR PATIENT HAS A PD?
Evaluate these two areas

Identifying patients who have PDs in primary care is useful for two reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother clinician-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the clinician-­patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FPP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the clinician-patient relationship
The interpersonal dysfunction of patients with PDs will often surface in the clinician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FPP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the clinician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the clinician’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios? Bringing up a potential diagnosis of PD may be a delicate matter for the FPP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FPP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Continue for forms of psychotherapy >>

EVIDENCE SUPPORTS TWO FORMS OF PSYCHOTHERAPY
Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The two major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (> 12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

MEDICATION MIGHT IMPROVE SYMPTOMS, NOT PERSONALITY DEFICITS
Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and ­affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned clinicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction and are best used symptomatically as adjuncts to psychotherapy.^28,30

Next page: Steps to take during the office visit >>

STEPS YOU CAN TAKE DURING THE OFFICE VISIT
Although it is not feasible for most FPPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the clinician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the clinician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a clinician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.                           

Based on Bob’s history of interpersonal conflicts and perceived persecution by coworkers, the FPP consults with a psychotherapist colleague, who says Bob’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Bob refuses to see a therapist, his FPP decides to focus on promoting small improvements in Bob’s interpersonal interactions and reducing absenteeism at work.

The FPP validates Bob’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FPP feels uneasy and reluctant to engage with Bob, who likely evokes such feelings to keep others at a distance. The FPP tactfully seeks to remain Bob’s ally without endorsing his distorted interpretation of events. Given Bob’s paranoid rejection of therapy, the FPP refrains from making further such recommendations. The FPP’s interventions, however, may help Bob warm to the idea of further help over time, and the FPP’s supportive stance will help to ameliorate the patient’s distress. (Additional examples of how to use the strategies described in this article can be found in Table 2.)

References on following page >>

REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
2. Hahn SR, Thompson KS, Wills TA, et al. The difficult clinician-patient relationship: somatization, personality and psychopathology. J Clin Epidemiol. 1994:47:647-657.
3. Schafer S, Nowlis DP. Personality disorders among difficult patients. Arch Fam Med. 1998;7:126-129.
4. Paris J. Estimating the prevalence of personality disorders in the community. J Pers Disord. 2010;24:405-411.
5. Newton-Howes G, Tyrer P, Anagnostakis K, et al. The prevalence of personality disorder, its comorbidity with mental state disorders, and its clinical significance in community mental health teams. Soc Psychiatry Psychiatr Epidemiol. 2010;45:453-460.
6. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
7. Moran P, Jenkins R, Tylee A, et al. The prevalence of personality disorder among UK primary care attenders. Acta Psychiatr Scand. 2000;102:52-57.
8. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: Meta-analysis of published studies. Br J Psychiatry. 2006;188:13-20.
9. Blasco-Fontecilla H, Baca-Garcia E, Dervic K, et al. Severity of personality disorders and suicide attempt. Acta Psychiatr Scand. 2009;119:149-155.
10. Colpaert K, Vanderplasschen W, De Maeyer J, et al. Prevalence and determinants of personality disorders in a clinical sample of alcohol-, drug-, and dual-dependent patients. Subst Use Misuse. 2012;47:649-661.
11. Yu R, Geddes JR, Fazel S. Personality disorders, violence, and antisocial behavior: A systematic review and meta-regression analysis. J Pers Disord. 2012;26:775-792.
12. Frankenburg FR, Zanarini MC. The association between borderline personality disorder and chronic medical illnesses, poor health-related lifestyle choices, and costly forms of health care utilization. J Clin Psychiatry. 2004;65:1660-1665.
13. Lee HB, Bienvenu OJ, Cho SJ, et al. Personality disorders and traits as predictors of incident cardiovascular disease: Findings from the 23-year follow-up of the Baltimore ECA Study. Psychosomatics. 2010;51:289-296.
14. Skodol AE, Gunderson JG, McGlashan TH, et al. Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159:276-283.
15. Bender DS, Dolan RT, Skodol AE, et al. Treatment utilization by patients with personality disorders. Am J Psychiatry. 2001;158:295-302.
16. Livesley WJ. An empirically-based classification of personality disorder.
J Pers Disord. 2011;25:397-420.
17. Bender DS, Morey LC, Skodol AE. Toward a model for assessing personality functioning in DSM-5, part I: a review of theory and methods. J Pers Assess. 2011;93:332-346.
18. Fonagy P, Gergely G, Jurist EL, et al. Affect Regulation, Mentalization, and the Development of the Self. New York, NY: Other Press; 2002.
19. Yen S, Shea MT, Battle CL, et al. Traumatic exposure and posttraumatic stress disorder in borderline, schizotypal, avoidant, and obsessive-compulsive personality disorders: findings from the collaborative longitudinal personality disorders study. J Nerv Ment Dis. 2002;190:510-518.
20. Morey LC, Stagner BH. Narcissistic pathology as core personality dysfunction: comparing DSM-IV and the DSM-5 proposal for narcissistic personality disorder. J Clin Psychol. 2012;68:908-921.
21. Lynch TR, Chapman AL, Rosenthal MZ, et al. Mechanisms of change in dialectical behaviour therapy: theoretical and empirical observations.
J Clin Psychol. 2006;62:459-480.
22. Kliem S, Kröger C, Kosfelder J. Dialectical behavior therapy for borderline personality disorder: a meta-analysis using mixed-effects modeling.
J Consult Clin Psychol. 2010;78:936-951.
23. Clarkin JF, Levy KN, Lenzenweger MF, et al. Evaluating three treatments for borderline personality disorder: a multiwave study. Am J Psychiatry. 2007;164:922-928.
24. Gregory RJ, DeLucia-Deranja E, Mogle JA. Dynamic deconstructive psychotherapy versus optimized community care for borderline personality disorder co-occurring with alcohol use disorders: a 30-month follow-up. J Nerv Ment Dis. 2010;198:292-298.
25. Bateman A, Fonagy P. Randomized controlled trial of outpatient mentalization-based treatment versus structured clinical management for borderline personality disorder. Am J Psychiatry. 2009;166:1355-1364.
26. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
27. Ogrodniczuk JS, Piper WE. Day treatment for personality disorders: a review of research findings. Harv Rev Psychiatry. 2001;9:105-117.
28. Paris J. Pharmacological treatments for personality disorders. Int Rev Psychiatry. 2011;23:303-309.
29. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
30. Steinberg PI. The use of low-dose neuroleptics in the treatment of patients with severe personality disorder: An adjunct to psychotherapy. BCMJ. 2007;49:306-310.
31. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo controlled pilot study. J Clin Psychiatry. 2001;62:849-854.
32. Nickel MK, Loew TH, Pedrosa Gil F. Aripiprazole in treatment of borderline patients, part II: an 18-month follow up. Psychopharmacology (Berl). 2007;191:1023-1026.
33. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
34. Linehan MM, Dimeff LA, Reynolds SK, et al. Dialectal behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder. Drug Alcohol Depend. 2002;67:13-26.
35. Rossberg JI, Karterud S, Pedersen G, et al. An empirical study of countertransference reactions toward patients with personality disorders. Compr Psychiatry. 2007;48:225-230.

If Bob were your patient, how would you proceed? 

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the clinician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the clinician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

Next page: How common are PDs?

PDs ARE MORE COMMON THAN YOU MIGHT SUSPECT
The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (see Table 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually have several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

What to do if you suspect your patient has a PD >>

SUSPECT YOUR PATIENT HAS A PD?
Evaluate these two areas

Identifying patients who have PDs in primary care is useful for two reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother clinician-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the clinician-­patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FPP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the clinician-patient relationship
The interpersonal dysfunction of patients with PDs will often surface in the clinician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FPP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the clinician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the clinician’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios? Bringing up a potential diagnosis of PD may be a delicate matter for the FPP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FPP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Continue for forms of psychotherapy >>

EVIDENCE SUPPORTS TWO FORMS OF PSYCHOTHERAPY
Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The two major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (> 12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

MEDICATION MIGHT IMPROVE SYMPTOMS, NOT PERSONALITY DEFICITS
Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and ­affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned clinicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction and are best used symptomatically as adjuncts to psychotherapy.^28,30

Next page: Steps to take during the office visit >>

STEPS YOU CAN TAKE DURING THE OFFICE VISIT
Although it is not feasible for most FPPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the clinician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the clinician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a clinician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.                           

Based on Bob’s history of interpersonal conflicts and perceived persecution by coworkers, the FPP consults with a psychotherapist colleague, who says Bob’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Bob refuses to see a therapist, his FPP decides to focus on promoting small improvements in Bob’s interpersonal interactions and reducing absenteeism at work.

The FPP validates Bob’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FPP feels uneasy and reluctant to engage with Bob, who likely evokes such feelings to keep others at a distance. The FPP tactfully seeks to remain Bob’s ally without endorsing his distorted interpretation of events. Given Bob’s paranoid rejection of therapy, the FPP refrains from making further such recommendations. The FPP’s interventions, however, may help Bob warm to the idea of further help over time, and the FPP’s supportive stance will help to ameliorate the patient’s distress. (Additional examples of how to use the strategies described in this article can be found in Table 2.)

References on following page >>

REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
2. Hahn SR, Thompson KS, Wills TA, et al. The difficult clinician-patient relationship: somatization, personality and psychopathology. J Clin Epidemiol. 1994:47:647-657.
3. Schafer S, Nowlis DP. Personality disorders among difficult patients. Arch Fam Med. 1998;7:126-129.
4. Paris J. Estimating the prevalence of personality disorders in the community. J Pers Disord. 2010;24:405-411.
5. Newton-Howes G, Tyrer P, Anagnostakis K, et al. The prevalence of personality disorder, its comorbidity with mental state disorders, and its clinical significance in community mental health teams. Soc Psychiatry Psychiatr Epidemiol. 2010;45:453-460.
6. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
7. Moran P, Jenkins R, Tylee A, et al. The prevalence of personality disorder among UK primary care attenders. Acta Psychiatr Scand. 2000;102:52-57.
8. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: Meta-analysis of published studies. Br J Psychiatry. 2006;188:13-20.
9. Blasco-Fontecilla H, Baca-Garcia E, Dervic K, et al. Severity of personality disorders and suicide attempt. Acta Psychiatr Scand. 2009;119:149-155.
10. Colpaert K, Vanderplasschen W, De Maeyer J, et al. Prevalence and determinants of personality disorders in a clinical sample of alcohol-, drug-, and dual-dependent patients. Subst Use Misuse. 2012;47:649-661.
11. Yu R, Geddes JR, Fazel S. Personality disorders, violence, and antisocial behavior: A systematic review and meta-regression analysis. J Pers Disord. 2012;26:775-792.
12. Frankenburg FR, Zanarini MC. The association between borderline personality disorder and chronic medical illnesses, poor health-related lifestyle choices, and costly forms of health care utilization. J Clin Psychiatry. 2004;65:1660-1665.
13. Lee HB, Bienvenu OJ, Cho SJ, et al. Personality disorders and traits as predictors of incident cardiovascular disease: Findings from the 23-year follow-up of the Baltimore ECA Study. Psychosomatics. 2010;51:289-296.
14. Skodol AE, Gunderson JG, McGlashan TH, et al. Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159:276-283.
15. Bender DS, Dolan RT, Skodol AE, et al. Treatment utilization by patients with personality disorders. Am J Psychiatry. 2001;158:295-302.
16. Livesley WJ. An empirically-based classification of personality disorder.
J Pers Disord. 2011;25:397-420.
17. Bender DS, Morey LC, Skodol AE. Toward a model for assessing personality functioning in DSM-5, part I: a review of theory and methods. J Pers Assess. 2011;93:332-346.
18. Fonagy P, Gergely G, Jurist EL, et al. Affect Regulation, Mentalization, and the Development of the Self. New York, NY: Other Press; 2002.
19. Yen S, Shea MT, Battle CL, et al. Traumatic exposure and posttraumatic stress disorder in borderline, schizotypal, avoidant, and obsessive-compulsive personality disorders: findings from the collaborative longitudinal personality disorders study. J Nerv Ment Dis. 2002;190:510-518.
20. Morey LC, Stagner BH. Narcissistic pathology as core personality dysfunction: comparing DSM-IV and the DSM-5 proposal for narcissistic personality disorder. J Clin Psychol. 2012;68:908-921.
21. Lynch TR, Chapman AL, Rosenthal MZ, et al. Mechanisms of change in dialectical behaviour therapy: theoretical and empirical observations.
J Clin Psychol. 2006;62:459-480.
22. Kliem S, Kröger C, Kosfelder J. Dialectical behavior therapy for borderline personality disorder: a meta-analysis using mixed-effects modeling.
J Consult Clin Psychol. 2010;78:936-951.
23. Clarkin JF, Levy KN, Lenzenweger MF, et al. Evaluating three treatments for borderline personality disorder: a multiwave study. Am J Psychiatry. 2007;164:922-928.
24. Gregory RJ, DeLucia-Deranja E, Mogle JA. Dynamic deconstructive psychotherapy versus optimized community care for borderline personality disorder co-occurring with alcohol use disorders: a 30-month follow-up. J Nerv Ment Dis. 2010;198:292-298.
25. Bateman A, Fonagy P. Randomized controlled trial of outpatient mentalization-based treatment versus structured clinical management for borderline personality disorder. Am J Psychiatry. 2009;166:1355-1364.
26. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
27. Ogrodniczuk JS, Piper WE. Day treatment for personality disorders: a review of research findings. Harv Rev Psychiatry. 2001;9:105-117.
28. Paris J. Pharmacological treatments for personality disorders. Int Rev Psychiatry. 2011;23:303-309.
29. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
30. Steinberg PI. The use of low-dose neuroleptics in the treatment of patients with severe personality disorder: An adjunct to psychotherapy. BCMJ. 2007;49:306-310.
31. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo controlled pilot study. J Clin Psychiatry. 2001;62:849-854.
32. Nickel MK, Loew TH, Pedrosa Gil F. Aripiprazole in treatment of borderline patients, part II: an 18-month follow up. Psychopharmacology (Berl). 2007;191:1023-1026.
33. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
34. Linehan MM, Dimeff LA, Reynolds SK, et al. Dialectal behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder. Drug Alcohol Depend. 2002;67:13-26.
35. Rossberg JI, Karterud S, Pedersen G, et al. An empirical study of countertransference reactions toward patients with personality disorders. Compr Psychiatry. 2007;48:225-230.

If Bob were your patient, how would you proceed? 

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the clinician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the clinician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

Next page: How common are PDs?

PDs ARE MORE COMMON THAN YOU MIGHT SUSPECT
The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (see Table 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually have several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

What to do if you suspect your patient has a PD >>

SUSPECT YOUR PATIENT HAS A PD?
Evaluate these two areas

Identifying patients who have PDs in primary care is useful for two reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother clinician-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the clinician-­patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FPP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the clinician-patient relationship
The interpersonal dysfunction of patients with PDs will often surface in the clinician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FPP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the clinician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the clinician’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios? Bringing up a potential diagnosis of PD may be a delicate matter for the FPP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FPP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Continue for forms of psychotherapy >>

EVIDENCE SUPPORTS TWO FORMS OF PSYCHOTHERAPY
Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The two major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (> 12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

MEDICATION MIGHT IMPROVE SYMPTOMS, NOT PERSONALITY DEFICITS
Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and ­affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned clinicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction and are best used symptomatically as adjuncts to psychotherapy.^28,30

Next page: Steps to take during the office visit >>

STEPS YOU CAN TAKE DURING THE OFFICE VISIT
Although it is not feasible for most FPPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the clinician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the clinician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a clinician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.                           

Based on Bob’s history of interpersonal conflicts and perceived persecution by coworkers, the FPP consults with a psychotherapist colleague, who says Bob’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Bob refuses to see a therapist, his FPP decides to focus on promoting small improvements in Bob’s interpersonal interactions and reducing absenteeism at work.

The FPP validates Bob’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FPP feels uneasy and reluctant to engage with Bob, who likely evokes such feelings to keep others at a distance. The FPP tactfully seeks to remain Bob’s ally without endorsing his distorted interpretation of events. Given Bob’s paranoid rejection of therapy, the FPP refrains from making further such recommendations. The FPP’s interventions, however, may help Bob warm to the idea of further help over time, and the FPP’s supportive stance will help to ameliorate the patient’s distress. (Additional examples of how to use the strategies described in this article can be found in Table 2.)

References on following page >>

REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
2. Hahn SR, Thompson KS, Wills TA, et al. The difficult clinician-patient relationship: somatization, personality and psychopathology. J Clin Epidemiol. 1994:47:647-657.
3. Schafer S, Nowlis DP. Personality disorders among difficult patients. Arch Fam Med. 1998;7:126-129.
4. Paris J. Estimating the prevalence of personality disorders in the community. J Pers Disord. 2010;24:405-411.
5. Newton-Howes G, Tyrer P, Anagnostakis K, et al. The prevalence of personality disorder, its comorbidity with mental state disorders, and its clinical significance in community mental health teams. Soc Psychiatry Psychiatr Epidemiol. 2010;45:453-460.
6. Zimmerman M, Rothschild L, Chelminski I. The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry. 2005;162:1911-1918.
7. Moran P, Jenkins R, Tylee A, et al. The prevalence of personality disorder among UK primary care attenders. Acta Psychiatr Scand. 2000;102:52-57.
8. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: Meta-analysis of published studies. Br J Psychiatry. 2006;188:13-20.
9. Blasco-Fontecilla H, Baca-Garcia E, Dervic K, et al. Severity of personality disorders and suicide attempt. Acta Psychiatr Scand. 2009;119:149-155.
10. Colpaert K, Vanderplasschen W, De Maeyer J, et al. Prevalence and determinants of personality disorders in a clinical sample of alcohol-, drug-, and dual-dependent patients. Subst Use Misuse. 2012;47:649-661.
11. Yu R, Geddes JR, Fazel S. Personality disorders, violence, and antisocial behavior: A systematic review and meta-regression analysis. J Pers Disord. 2012;26:775-792.
12. Frankenburg FR, Zanarini MC. The association between borderline personality disorder and chronic medical illnesses, poor health-related lifestyle choices, and costly forms of health care utilization. J Clin Psychiatry. 2004;65:1660-1665.
13. Lee HB, Bienvenu OJ, Cho SJ, et al. Personality disorders and traits as predictors of incident cardiovascular disease: Findings from the 23-year follow-up of the Baltimore ECA Study. Psychosomatics. 2010;51:289-296.
14. Skodol AE, Gunderson JG, McGlashan TH, et al. Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry. 2002;159:276-283.
15. Bender DS, Dolan RT, Skodol AE, et al. Treatment utilization by patients with personality disorders. Am J Psychiatry. 2001;158:295-302.
16. Livesley WJ. An empirically-based classification of personality disorder.
J Pers Disord. 2011;25:397-420.
17. Bender DS, Morey LC, Skodol AE. Toward a model for assessing personality functioning in DSM-5, part I: a review of theory and methods. J Pers Assess. 2011;93:332-346.
18. Fonagy P, Gergely G, Jurist EL, et al. Affect Regulation, Mentalization, and the Development of the Self. New York, NY: Other Press; 2002.
19. Yen S, Shea MT, Battle CL, et al. Traumatic exposure and posttraumatic stress disorder in borderline, schizotypal, avoidant, and obsessive-compulsive personality disorders: findings from the collaborative longitudinal personality disorders study. J Nerv Ment Dis. 2002;190:510-518.
20. Morey LC, Stagner BH. Narcissistic pathology as core personality dysfunction: comparing DSM-IV and the DSM-5 proposal for narcissistic personality disorder. J Clin Psychol. 2012;68:908-921.
21. Lynch TR, Chapman AL, Rosenthal MZ, et al. Mechanisms of change in dialectical behaviour therapy: theoretical and empirical observations.
J Clin Psychol. 2006;62:459-480.
22. Kliem S, Kröger C, Kosfelder J. Dialectical behavior therapy for borderline personality disorder: a meta-analysis using mixed-effects modeling.
J Consult Clin Psychol. 2010;78:936-951.
23. Clarkin JF, Levy KN, Lenzenweger MF, et al. Evaluating three treatments for borderline personality disorder: a multiwave study. Am J Psychiatry. 2007;164:922-928.
24. Gregory RJ, DeLucia-Deranja E, Mogle JA. Dynamic deconstructive psychotherapy versus optimized community care for borderline personality disorder co-occurring with alcohol use disorders: a 30-month follow-up. J Nerv Ment Dis. 2010;198:292-298.
25. Bateman A, Fonagy P. Randomized controlled trial of outpatient mentalization-based treatment versus structured clinical management for borderline personality disorder. Am J Psychiatry. 2009;166:1355-1364.
26. McMain SF, Links PS, Gnam WH, et al. A randomized trial of dialectical behavior therapy versus general psychiatric management for borderline personality disorder. Am J Psychiatry. 2009;166:1365-1374.
27. Ogrodniczuk JS, Piper WE. Day treatment for personality disorders: a review of research findings. Harv Rev Psychiatry. 2001;9:105-117.
28. Paris J. Pharmacological treatments for personality disorders. Int Rev Psychiatry. 2011;23:303-309.
29. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14:1257-1288.
30. Steinberg PI. The use of low-dose neuroleptics in the treatment of patients with severe personality disorder: An adjunct to psychotherapy. BCMJ. 2007;49:306-310.
31. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo controlled pilot study. J Clin Psychiatry. 2001;62:849-854.
32. Nickel MK, Loew TH, Pedrosa Gil F. Aripiprazole in treatment of borderline patients, part II: an 18-month follow up. Psychopharmacology (Berl). 2007;191:1023-1026.
33. Silk KR. The process of managing medications in patients with borderline personality disorder. J Psychiatr Pract. 2011;17:311-319.
34. Linehan MM, Dimeff LA, Reynolds SK, et al. Dialectal behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder. Drug Alcohol Depend. 2002;67:13-26.
35. Rossberg JI, Karterud S, Pedersen G, et al. An empirical study of countertransference reactions toward patients with personality disorders. Compr Psychiatry. 2007;48:225-230.

A 58-year-old man presented to the emergency department (ED) via emergency medical services (EMS) with shortness of breath, lightheadedness, and nausea. Upon arrival to the ED, most of his symptoms had resolved. The patient reported that he had taken a two-hour flight into town the previous day and had spent an uneventful evening at a local hotel. He said that he began experiencing shortness of breath and lightheadedness soon after entering his rental vehicle an hour prior to presentation, explaining that he felt as if he “could not get any air.”

He denied chest pain, leg pain or swelling, abdominal pain, or recent illness. Medical history was significant for hypertension, for which he was taking losartan and amlodipine. He had no drug allergies, surgical history, or smoking history. Of note, when the hotel clerk got in the same rental vehicle to move it, he developed symptoms similar to those of the patient. As with the patient, the clerk’s symptoms quickly resolved after he got out of the vehicle.

The patient’s vital signs at examination included an oral temperature of 97.5°F; pulse, 62 beats/min; respiratory rate (RR), 18 breaths/min; blood pressure, 133/83 mm Hg; and O₂ saturation, 100% on room air. He was alert and oriented, in no distress, easily conversational, and without diaphoresis. The lungs were clear to auscultation bilaterally, and there was no calf swelling, tenderness, or palpable cords. The remainder of the physical exam was normal.

Ancillary studies included a normal chest X-ray. An ECG demonstrated sinus bradycardia with a rate of 56 beats/min but no evidence of ischemia or right heart strain. Complete blood count, troponin I, D-dimer, and creatine phosphokinase (CPK) with MB fraction levels were all within normal limits. A serum chemistry panel was also within normal limits, except for a serum glucose level of 181 mg/dL. Venous co-oximetry showed a carboxyhemoglobin level of 0.0, and methemoglobin level of 0.5 gm% (normal range, 0.4-1.5).

Since both the patient’s and hotel clerk’s symptoms started when each was in the rental car, the patient was questioned about the vehicle and its contents. The car was a late-model rental in good condition per report. The patient informed the treating emergency physician that he worked as a decorative cake salesman and had brought cake samples with him to display at a trade show. He further stated that he had left these samples in the car overnight, packed in dry ice.

What's the solution to this unusual case?

Upon learning this information, EMS was contacted and instructed to return to the hotel and rental vehicle. The hotel room was noted to have normal levels of O₂ and carbon monoxide (CO) on measurement. Investigation of the car revealed normal levels of CO but O₂ levels too low to read on the sensor. The emergency team concluded that the dry ice (the solid form of carbon dioxide [CO₂]) sublimed to CO₂ gas overnight. This displaced the O₂ in the vehicle, resulting in severe hypoxia and the symptoms of both the patient and hotel clerk.

The patient was initially placed on 15 L of O₂ via a nonrebreather mask, then switched to 2 L of O₂ via nasal cannula. He was observed for a total of four hours after arrival; as he remained symptom-free, he was discharged home. Postdischarge follow-up information was not obtainable.

DISCUSSION
Carbon dioxide is prevalent in everyday life, from an agent in fire extinguishers and carbonation in beverages to byproducts of cellular metabolism. Similar to CO, it is a colorless and odorless gas.

Carbon dioxide is commonly used in the food industry as dry ice to keep items cold. In its solid state, CO₂ can cause severe frostbite with direct contact, similar to a burn. However, when dry ice is warmed and sublimated to a gaseous state, large amounts of CO₂ are generated, and this heavy gas can accumulate and displace air (ie, atmospheric O₂), especially in confined spaces. In low concentrations, gaseous CO₂ appears to have minimal toxicologic effects, but at higher concentrations it can cause tachycardia, tachypnea, dyspnea, visual disturbances, arrhythmias, impaired levels of consciousness, and death.

Carbon dioxide primarily acts as a simple asphyxiant, but it also dissolves in serum as carbonic acid, resulting in a metabolic acidosis. Compensation for this acidosis is accomplished by an increased RR (ie, respiratory alkalosis), which further worsens the intake of CO₂.^1,2

The normal concentration of CO₂ in the atmosphere is approximately 0.04% (396 ppm). The Occupational Safety and Health Administration (OSHA) has set a maximum safe exposure level of CO₂ at 0.5% (5,000 ppm) over an eight-hour day.³ Concentrations as low as 1% (10,000 ppm) may cause drowsiness. Exposure to concentrations of 7% to 10% for several minutes to an hour results in headache, tachycardia, dyspnea, and hyperventilation. At levels of 10% to 15%, dizziness, severe muscle twitching, and loss of consciousness can occur after only a few minutes. Death occurs within minutes at concentrations greater than 30%.²

Carbon dioxide also acts as a potent cerebral vasodilator, which may explain symptoms such as headache and dizziness.² The severity of symptoms is dependent on the concentration of CO₂, the length of the exposure, and the underlying health of the patient. Elevated concentrations of CO₂ can occur in areas where there is limited or poor ventilation, such as in a mine (where it is known as blackdamp, stythe, or choke damp),⁴ submarine, grain silo, or a sealed building without mechanical ventilation.

Continue for other case presentations >>

Other case presentations
Similar cases have been described in the literature. In one case, following Hurricane Ivan, a 34-year-old man placed four 25-pound blocks of dry ice wrapped in paper in the front seat of his truck with the windows closed.⁵ After driving less than one-quarter of a mile, he developed dyspnea and telephoned for help before losing consciousness. Fortunately, he was found in time and recovered soon after the doors to his truck were opened.⁵

In another case, a 59-year-old man entered a walk-in freezer that contained dry ice wrapped loosely in plastic. He was found inside the freezer 20 minutes later in cardiac arrest; resuscitation efforts were unsuccessful. Investigation of the freezer found an initial O₂ concentration of 13% (normal level, 20.93%) and an estimated CO₂ level of 40%.⁵

Similarly, a 35-year-old woman was inadvertently locked in a bank vault while storing receipts. In a bid for help, she pulled the fire alarm, which triggered a CO₂-based fire-extinguishing system. The fire department responded and found the woman dead in the vault 30 minutes later. The cause of death was labeled as CO₂ intoxication.⁶

Natural phenomena
There have also been documented cases of CO₂ toxicity associated with volcanic eruption and other natural phenomena; for example, the Lake Nyos, Cameroon, West Africa incident in 1986. In this event, a magma pocket underlying the lake saturated the water with CO₂ stored as carbonic acid in the water. When a landslide hit the lake, it caused the carbonic acid stored in the depths of the lake to be upheaved to the surface, where it turned back into CO₂ and was released into the atmosphere. Since CO₂ is heavier than O₂, it displaced the O₂ near the ground, resulting in the suffocation and death of 1,700 people in the surrounding villages.²

Next page: Differential diagnosis >>

Differential diagnosis
When CO₂ toxicity is suspected, other conditions should be considered, as there may be more than one process involved. For example, other causes of coma or dyspnea should be investigated, including trauma, hypoglycemia, CO, methemoglobinemia, or other metabolic processes. In addition, a patient may have a pre-existing condition, such as a trauma or an altered mental status due to drugs or alcohol, all of which can increase his or her susceptibility to the effects of CO₂.

Evaluation and treatment
Useful laboratory testing includes arterial blood gas, venous co-oximetry for carboxyhemoglobin, chemistry panels, ethanol testing, and radiographs or CT, as indicated.

Initial management of suspected CO₂ toxicity entails first removing the patient from the source of the gas. Rescuers must exercise caution so as to prevent a mass-casualty incident. Once out of the dangerous environment, as long as the patient is conscious and spontaneously breathing, supportive measures are generally all that are necessary. Oxygen should be applied, after which the spontaneously breathing patient without underlying lung disease should rapidly return to normal.

If there is marked decrease in mental status or poor respiratory drive despite O₂ administration, intubation with mechanical ventilation may be required. A higher-than-normal RR will help remove excessive CO₂ in this instance.

If a respiratory acidosis is present, IV sodium bicarbonate should be avoided, as this may increase the level of serum CO₂. IV fluids and other supportive measures, including treatment for any concurrent conditions, may be indicated.

REFERENCES
1. Nelson LS, Odujebe OA. Simple asphyxiants and pulmonary irritants. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies, 9th ed. New York, NY: McGraw-Hill; 2011:1644-1645.
2. Langford NJ. Carbon dioxide poisoning. Toxicol Rev. 2005;24(4):229-235.
3. Occupational Health and Safety Standards. Table Z-1, Limits for air contaminants. Occupational Safety and Health Administration Web site. www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=standards&p_id=9992. Accessed January 19, 2015.
4. Hedlund FH. The extreme carbon dioxide outburst at the Menzengraben potash mine 7 July 1953. Safety Sci. 2012;50(3):537-553.
5. Dunford JV, Lucas J, Vent N, et al. Asphyxiation due to dry ice in a walk-in freezer. ­ J Emerg Med.­ 2009;36(4):353-356.
6. Gill JR, Ely SF, Hua Z. Environmental gas displacement: three accidental deaths in the workplace. Am J Forensic Med Pathol. 2002;23(1):26-30.

A 58-year-old man presented to the emergency department (ED) via emergency medical services (EMS) with shortness of breath, lightheadedness, and nausea. Upon arrival to the ED, most of his symptoms had resolved. The patient reported that he had taken a two-hour flight into town the previous day and had spent an uneventful evening at a local hotel. He said that he began experiencing shortness of breath and lightheadedness soon after entering his rental vehicle an hour prior to presentation, explaining that he felt as if he “could not get any air.”

He denied chest pain, leg pain or swelling, abdominal pain, or recent illness. Medical history was significant for hypertension, for which he was taking losartan and amlodipine. He had no drug allergies, surgical history, or smoking history. Of note, when the hotel clerk got in the same rental vehicle to move it, he developed symptoms similar to those of the patient. As with the patient, the clerk’s symptoms quickly resolved after he got out of the vehicle.

The patient’s vital signs at examination included an oral temperature of 97.5°F; pulse, 62 beats/min; respiratory rate (RR), 18 breaths/min; blood pressure, 133/83 mm Hg; and O₂ saturation, 100% on room air. He was alert and oriented, in no distress, easily conversational, and without diaphoresis. The lungs were clear to auscultation bilaterally, and there was no calf swelling, tenderness, or palpable cords. The remainder of the physical exam was normal.

Ancillary studies included a normal chest X-ray. An ECG demonstrated sinus bradycardia with a rate of 56 beats/min but no evidence of ischemia or right heart strain. Complete blood count, troponin I, D-dimer, and creatine phosphokinase (CPK) with MB fraction levels were all within normal limits. A serum chemistry panel was also within normal limits, except for a serum glucose level of 181 mg/dL. Venous co-oximetry showed a carboxyhemoglobin level of 0.0, and methemoglobin level of 0.5 gm% (normal range, 0.4-1.5).

Since both the patient’s and hotel clerk’s symptoms started when each was in the rental car, the patient was questioned about the vehicle and its contents. The car was a late-model rental in good condition per report. The patient informed the treating emergency physician that he worked as a decorative cake salesman and had brought cake samples with him to display at a trade show. He further stated that he had left these samples in the car overnight, packed in dry ice.

What's the solution to this unusual case?

Upon learning this information, EMS was contacted and instructed to return to the hotel and rental vehicle. The hotel room was noted to have normal levels of O₂ and carbon monoxide (CO) on measurement. Investigation of the car revealed normal levels of CO but O₂ levels too low to read on the sensor. The emergency team concluded that the dry ice (the solid form of carbon dioxide [CO₂]) sublimed to CO₂ gas overnight. This displaced the O₂ in the vehicle, resulting in severe hypoxia and the symptoms of both the patient and hotel clerk.

The patient was initially placed on 15 L of O₂ via a nonrebreather mask, then switched to 2 L of O₂ via nasal cannula. He was observed for a total of four hours after arrival; as he remained symptom-free, he was discharged home. Postdischarge follow-up information was not obtainable.

DISCUSSION
Carbon dioxide is prevalent in everyday life, from an agent in fire extinguishers and carbonation in beverages to byproducts of cellular metabolism. Similar to CO, it is a colorless and odorless gas.

Carbon dioxide is commonly used in the food industry as dry ice to keep items cold. In its solid state, CO₂ can cause severe frostbite with direct contact, similar to a burn. However, when dry ice is warmed and sublimated to a gaseous state, large amounts of CO₂ are generated, and this heavy gas can accumulate and displace air (ie, atmospheric O₂), especially in confined spaces. In low concentrations, gaseous CO₂ appears to have minimal toxicologic effects, but at higher concentrations it can cause tachycardia, tachypnea, dyspnea, visual disturbances, arrhythmias, impaired levels of consciousness, and death.

Carbon dioxide primarily acts as a simple asphyxiant, but it also dissolves in serum as carbonic acid, resulting in a metabolic acidosis. Compensation for this acidosis is accomplished by an increased RR (ie, respiratory alkalosis), which further worsens the intake of CO₂.^1,2

The normal concentration of CO₂ in the atmosphere is approximately 0.04% (396 ppm). The Occupational Safety and Health Administration (OSHA) has set a maximum safe exposure level of CO₂ at 0.5% (5,000 ppm) over an eight-hour day.³ Concentrations as low as 1% (10,000 ppm) may cause drowsiness. Exposure to concentrations of 7% to 10% for several minutes to an hour results in headache, tachycardia, dyspnea, and hyperventilation. At levels of 10% to 15%, dizziness, severe muscle twitching, and loss of consciousness can occur after only a few minutes. Death occurs within minutes at concentrations greater than 30%.²

Carbon dioxide also acts as a potent cerebral vasodilator, which may explain symptoms such as headache and dizziness.² The severity of symptoms is dependent on the concentration of CO₂, the length of the exposure, and the underlying health of the patient. Elevated concentrations of CO₂ can occur in areas where there is limited or poor ventilation, such as in a mine (where it is known as blackdamp, stythe, or choke damp),⁴ submarine, grain silo, or a sealed building without mechanical ventilation.

Continue for other case presentations >>

Other case presentations
Similar cases have been described in the literature. In one case, following Hurricane Ivan, a 34-year-old man placed four 25-pound blocks of dry ice wrapped in paper in the front seat of his truck with the windows closed.⁵ After driving less than one-quarter of a mile, he developed dyspnea and telephoned for help before losing consciousness. Fortunately, he was found in time and recovered soon after the doors to his truck were opened.⁵

In another case, a 59-year-old man entered a walk-in freezer that contained dry ice wrapped loosely in plastic. He was found inside the freezer 20 minutes later in cardiac arrest; resuscitation efforts were unsuccessful. Investigation of the freezer found an initial O₂ concentration of 13% (normal level, 20.93%) and an estimated CO₂ level of 40%.⁵

Similarly, a 35-year-old woman was inadvertently locked in a bank vault while storing receipts. In a bid for help, she pulled the fire alarm, which triggered a CO₂-based fire-extinguishing system. The fire department responded and found the woman dead in the vault 30 minutes later. The cause of death was labeled as CO₂ intoxication.⁶

Natural phenomena
There have also been documented cases of CO₂ toxicity associated with volcanic eruption and other natural phenomena; for example, the Lake Nyos, Cameroon, West Africa incident in 1986. In this event, a magma pocket underlying the lake saturated the water with CO₂ stored as carbonic acid in the water. When a landslide hit the lake, it caused the carbonic acid stored in the depths of the lake to be upheaved to the surface, where it turned back into CO₂ and was released into the atmosphere. Since CO₂ is heavier than O₂, it displaced the O₂ near the ground, resulting in the suffocation and death of 1,700 people in the surrounding villages.²

Next page: Differential diagnosis >>

Differential diagnosis
When CO₂ toxicity is suspected, other conditions should be considered, as there may be more than one process involved. For example, other causes of coma or dyspnea should be investigated, including trauma, hypoglycemia, CO, methemoglobinemia, or other metabolic processes. In addition, a patient may have a pre-existing condition, such as a trauma or an altered mental status due to drugs or alcohol, all of which can increase his or her susceptibility to the effects of CO₂.

Evaluation and treatment
Useful laboratory testing includes arterial blood gas, venous co-oximetry for carboxyhemoglobin, chemistry panels, ethanol testing, and radiographs or CT, as indicated.

Initial management of suspected CO₂ toxicity entails first removing the patient from the source of the gas. Rescuers must exercise caution so as to prevent a mass-casualty incident. Once out of the dangerous environment, as long as the patient is conscious and spontaneously breathing, supportive measures are generally all that are necessary. Oxygen should be applied, after which the spontaneously breathing patient without underlying lung disease should rapidly return to normal.

If there is marked decrease in mental status or poor respiratory drive despite O₂ administration, intubation with mechanical ventilation may be required. A higher-than-normal RR will help remove excessive CO₂ in this instance.

If a respiratory acidosis is present, IV sodium bicarbonate should be avoided, as this may increase the level of serum CO₂. IV fluids and other supportive measures, including treatment for any concurrent conditions, may be indicated.

REFERENCES
1. Nelson LS, Odujebe OA. Simple asphyxiants and pulmonary irritants. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies, 9th ed. New York, NY: McGraw-Hill; 2011:1644-1645.
2. Langford NJ. Carbon dioxide poisoning. Toxicol Rev. 2005;24(4):229-235.
3. Occupational Health and Safety Standards. Table Z-1, Limits for air contaminants. Occupational Safety and Health Administration Web site. www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=standards&p_id=9992. Accessed January 19, 2015.
4. Hedlund FH. The extreme carbon dioxide outburst at the Menzengraben potash mine 7 July 1953. Safety Sci. 2012;50(3):537-553.
5. Dunford JV, Lucas J, Vent N, et al. Asphyxiation due to dry ice in a walk-in freezer. ­ J Emerg Med.­ 2009;36(4):353-356.
6. Gill JR, Ely SF, Hua Z. Environmental gas displacement: three accidental deaths in the workplace. Am J Forensic Med Pathol. 2002;23(1):26-30.

A 58-year-old man presented to the emergency department (ED) via emergency medical services (EMS) with shortness of breath, lightheadedness, and nausea. Upon arrival to the ED, most of his symptoms had resolved. The patient reported that he had taken a two-hour flight into town the previous day and had spent an uneventful evening at a local hotel. He said that he began experiencing shortness of breath and lightheadedness soon after entering his rental vehicle an hour prior to presentation, explaining that he felt as if he “could not get any air.”

He denied chest pain, leg pain or swelling, abdominal pain, or recent illness. Medical history was significant for hypertension, for which he was taking losartan and amlodipine. He had no drug allergies, surgical history, or smoking history. Of note, when the hotel clerk got in the same rental vehicle to move it, he developed symptoms similar to those of the patient. As with the patient, the clerk’s symptoms quickly resolved after he got out of the vehicle.

The patient’s vital signs at examination included an oral temperature of 97.5°F; pulse, 62 beats/min; respiratory rate (RR), 18 breaths/min; blood pressure, 133/83 mm Hg; and O₂ saturation, 100% on room air. He was alert and oriented, in no distress, easily conversational, and without diaphoresis. The lungs were clear to auscultation bilaterally, and there was no calf swelling, tenderness, or palpable cords. The remainder of the physical exam was normal.

Ancillary studies included a normal chest X-ray. An ECG demonstrated sinus bradycardia with a rate of 56 beats/min but no evidence of ischemia or right heart strain. Complete blood count, troponin I, D-dimer, and creatine phosphokinase (CPK) with MB fraction levels were all within normal limits. A serum chemistry panel was also within normal limits, except for a serum glucose level of 181 mg/dL. Venous co-oximetry showed a carboxyhemoglobin level of 0.0, and methemoglobin level of 0.5 gm% (normal range, 0.4-1.5).

Since both the patient’s and hotel clerk’s symptoms started when each was in the rental car, the patient was questioned about the vehicle and its contents. The car was a late-model rental in good condition per report. The patient informed the treating emergency physician that he worked as a decorative cake salesman and had brought cake samples with him to display at a trade show. He further stated that he had left these samples in the car overnight, packed in dry ice.

What's the solution to this unusual case?

Upon learning this information, EMS was contacted and instructed to return to the hotel and rental vehicle. The hotel room was noted to have normal levels of O₂ and carbon monoxide (CO) on measurement. Investigation of the car revealed normal levels of CO but O₂ levels too low to read on the sensor. The emergency team concluded that the dry ice (the solid form of carbon dioxide [CO₂]) sublimed to CO₂ gas overnight. This displaced the O₂ in the vehicle, resulting in severe hypoxia and the symptoms of both the patient and hotel clerk.

The patient was initially placed on 15 L of O₂ via a nonrebreather mask, then switched to 2 L of O₂ via nasal cannula. He was observed for a total of four hours after arrival; as he remained symptom-free, he was discharged home. Postdischarge follow-up information was not obtainable.

DISCUSSION
Carbon dioxide is prevalent in everyday life, from an agent in fire extinguishers and carbonation in beverages to byproducts of cellular metabolism. Similar to CO, it is a colorless and odorless gas.

Carbon dioxide is commonly used in the food industry as dry ice to keep items cold. In its solid state, CO₂ can cause severe frostbite with direct contact, similar to a burn. However, when dry ice is warmed and sublimated to a gaseous state, large amounts of CO₂ are generated, and this heavy gas can accumulate and displace air (ie, atmospheric O₂), especially in confined spaces. In low concentrations, gaseous CO₂ appears to have minimal toxicologic effects, but at higher concentrations it can cause tachycardia, tachypnea, dyspnea, visual disturbances, arrhythmias, impaired levels of consciousness, and death.

Carbon dioxide primarily acts as a simple asphyxiant, but it also dissolves in serum as carbonic acid, resulting in a metabolic acidosis. Compensation for this acidosis is accomplished by an increased RR (ie, respiratory alkalosis), which further worsens the intake of CO₂.^1,2

The normal concentration of CO₂ in the atmosphere is approximately 0.04% (396 ppm). The Occupational Safety and Health Administration (OSHA) has set a maximum safe exposure level of CO₂ at 0.5% (5,000 ppm) over an eight-hour day.³ Concentrations as low as 1% (10,000 ppm) may cause drowsiness. Exposure to concentrations of 7% to 10% for several minutes to an hour results in headache, tachycardia, dyspnea, and hyperventilation. At levels of 10% to 15%, dizziness, severe muscle twitching, and loss of consciousness can occur after only a few minutes. Death occurs within minutes at concentrations greater than 30%.²

Carbon dioxide also acts as a potent cerebral vasodilator, which may explain symptoms such as headache and dizziness.² The severity of symptoms is dependent on the concentration of CO₂, the length of the exposure, and the underlying health of the patient. Elevated concentrations of CO₂ can occur in areas where there is limited or poor ventilation, such as in a mine (where it is known as blackdamp, stythe, or choke damp),⁴ submarine, grain silo, or a sealed building without mechanical ventilation.

Continue for other case presentations >>

Other case presentations
Similar cases have been described in the literature. In one case, following Hurricane Ivan, a 34-year-old man placed four 25-pound blocks of dry ice wrapped in paper in the front seat of his truck with the windows closed.⁵ After driving less than one-quarter of a mile, he developed dyspnea and telephoned for help before losing consciousness. Fortunately, he was found in time and recovered soon after the doors to his truck were opened.⁵

In another case, a 59-year-old man entered a walk-in freezer that contained dry ice wrapped loosely in plastic. He was found inside the freezer 20 minutes later in cardiac arrest; resuscitation efforts were unsuccessful. Investigation of the freezer found an initial O₂ concentration of 13% (normal level, 20.93%) and an estimated CO₂ level of 40%.⁵

Similarly, a 35-year-old woman was inadvertently locked in a bank vault while storing receipts. In a bid for help, she pulled the fire alarm, which triggered a CO₂-based fire-extinguishing system. The fire department responded and found the woman dead in the vault 30 minutes later. The cause of death was labeled as CO₂ intoxication.⁶

Natural phenomena
There have also been documented cases of CO₂ toxicity associated with volcanic eruption and other natural phenomena; for example, the Lake Nyos, Cameroon, West Africa incident in 1986. In this event, a magma pocket underlying the lake saturated the water with CO₂ stored as carbonic acid in the water. When a landslide hit the lake, it caused the carbonic acid stored in the depths of the lake to be upheaved to the surface, where it turned back into CO₂ and was released into the atmosphere. Since CO₂ is heavier than O₂, it displaced the O₂ near the ground, resulting in the suffocation and death of 1,700 people in the surrounding villages.²

Next page: Differential diagnosis >>

Differential diagnosis
When CO₂ toxicity is suspected, other conditions should be considered, as there may be more than one process involved. For example, other causes of coma or dyspnea should be investigated, including trauma, hypoglycemia, CO, methemoglobinemia, or other metabolic processes. In addition, a patient may have a pre-existing condition, such as a trauma or an altered mental status due to drugs or alcohol, all of which can increase his or her susceptibility to the effects of CO₂.

Evaluation and treatment
Useful laboratory testing includes arterial blood gas, venous co-oximetry for carboxyhemoglobin, chemistry panels, ethanol testing, and radiographs or CT, as indicated.

Initial management of suspected CO₂ toxicity entails first removing the patient from the source of the gas. Rescuers must exercise caution so as to prevent a mass-casualty incident. Once out of the dangerous environment, as long as the patient is conscious and spontaneously breathing, supportive measures are generally all that are necessary. Oxygen should be applied, after which the spontaneously breathing patient without underlying lung disease should rapidly return to normal.

If there is marked decrease in mental status or poor respiratory drive despite O₂ administration, intubation with mechanical ventilation may be required. A higher-than-normal RR will help remove excessive CO₂ in this instance.

If a respiratory acidosis is present, IV sodium bicarbonate should be avoided, as this may increase the level of serum CO₂. IV fluids and other supportive measures, including treatment for any concurrent conditions, may be indicated.

REFERENCES
1. Nelson LS, Odujebe OA. Simple asphyxiants and pulmonary irritants. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies, 9th ed. New York, NY: McGraw-Hill; 2011:1644-1645.
2. Langford NJ. Carbon dioxide poisoning. Toxicol Rev. 2005;24(4):229-235.
3. Occupational Health and Safety Standards. Table Z-1, Limits for air contaminants. Occupational Safety and Health Administration Web site. www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=standards&p_id=9992. Accessed January 19, 2015.
4. Hedlund FH. The extreme carbon dioxide outburst at the Menzengraben potash mine 7 July 1953. Safety Sci. 2012;50(3):537-553.
5. Dunford JV, Lucas J, Vent N, et al. Asphyxiation due to dry ice in a walk-in freezer. ­ J Emerg Med.­ 2009;36(4):353-356.
6. Gill JR, Ely SF, Hua Z. Environmental gas displacement: three accidental deaths in the workplace. Am J Forensic Med Pathol. 2002;23(1):26-30.

Differences in bone size are established early in life, before puberty and perhaps even in utero.¹ Bone begins to form when mesenchymal cells form condensations—clusters of cells that adhere through expression of adhesion molecules² (Figure 1). Bone must be stiff, flexible enough to change shape to absorb energy, and light enough to allow mobility.^1,3 Longitudinal bone growth is detrimental to bone stability, but this effect is counteracted by concomitant bone growth in width.⁴ Bone growth in width has not been studied as extensively, despite its paramount role in skeletal development.⁵

Bone growth and development are products of the complex interactions of genetic and environmental factors, including diet, hormones, and mechanical stimuli.^6-9 Longitudinal bone growth is controlled by systemic and local hormones and local mechanical factors. Two models for control of bone growth in width have been suggested—the mechanostat theory (mechanical requirements regulate periosteal apposition) and the sizostat hypothesis (a master gene or set of genes regulates bone growth in width so bone reaches a preprogrammed size, independent of mechanical requirements).⁵

In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases¹⁰ and fracture risk.^11,12

Growth Plate

The growth plate consists mainly of collagen fibrils, proteoglycans, and water, arranged to form a sort of sponge with very small pores.¹³ The growth plate is located between epiphyseal and metaphyseal bone at the distal end of long bones¹⁴ and is strain-rate–dependent,^15,16 which means it is hard when squeezed rapidly but soft when deformed slowly. The growth plate becomes ossified after puberty and epiphyseal fusion.¹⁷

Histologically, the growth plate consists of horizontal zones of chondrocytes at different stages of differentiation.⁴ The germinal zone, at the epiphyseal end of the growth plate, contains resting chondrocytes, which seem crucial in orienting the underlying columns of chondrocytes and, therefore, in unidirectional bone growth, probably by secretion of a growth plate–orienting factor.^14,18 Next is the proliferative zone, a matrix-rich zone in which flattened chondrocytes undergo longitudinal cell division and orient themselves in typical column-wise fashion. At some point, proliferating chondrocytes lose their capacity to divide; they start to differentiate and become prehypertrophic, coinciding with a size increase.⁴ Proliferating chondrocytes are located in the transition (maturation or prehypertrophic) zone. In the hypertrophic zone, round chondrocytes secrete matrix proteins in large amounts.¹⁴ This stage is characterized by an increase in intracellular calcium concentration, which is essential in the production of matrix vesicles. These vesicles, small membrane-enclosed particles, are released from chondrocytes^19,20 and secrete calcium phosphates, hydroxyapatite, and matrix metalloproteinases, resulting in mineralization of the vesicles and their surrounding matrix.⁴ The chondrocytes in this mineralized zone eventually undergo programmed cell death (apoptosis), leaving a scaffold for new bone formation.

Longitudinal Bone Growth

Generally, bones increase in length as long as new material is being squeezed between the reserve zone of the growth plate and the zone of provisional calcification.⁴

Postnatal linear growth occurs in 3 phases. Phase 1 is characterized by a high rate of growth at the beginning of fetal life, and then rapid deceleration up to about 3 years; phase 2, by a lower, slowly decelerating growth rate up to puberty; and phase 3, by an increased rate of longitudinal growth until a peak is reached.^14,21,22

In 1964, Park²³ proposed that the structure of the epiphyseal cartilage may determine the pattern of the growing bone shaft. The changes within the hypertrophic zone are directly related to matrix mineralization, vascular invasion, and subsequent development.²⁴ Intracellular calcium concentration increases in the hypertrophic chondrocytes in the hypertrophic zone of growth plate cartilage; at some point, these chondrocytes begin to mineralize the longitudinal septa in the surrounding matrix²⁵ (Figure 2). At the growth cartilage junction, mononuclear cells of undetermined origin resorb the unmineralized horizontal septa of the growth cartilage. These cells are called septoclasts or chondroclasts.^25,26 Blood vessels invade the area and pave the way for bone cell precursors.²⁷ Eighty percent of the longitudinal septa of the growth cartilage is rapidly resorbed in the metaphyseal zone immediately behind the invading blood vessels, paving the way for bone cell precursors.²⁸ Fazzalari and colleagues²⁸ reported that about 40% of mineralized septa serves as scaffold for the formation of primary bone trabeculae; the other 60% is absorbed by chondroclasts (osteoclasts) near the vascular invasion front.

Regulation of Longitudinal Bone Growth

Longitudinal bone growth is regulated by genetic, hormonal, growth, and environment factors^17,29-31 (Table). It must be controlled on at least 3 different levels.⁴ Level 1 is systemic control by factors such as growth hormone (GH), sex hormones, and glucocorticoids. The major systemic hormones that control longitudinal bone growth during childhood are GH, insulin-like growth factor 1 (IGF-1), the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄), and glucocorticoids; during puberty, the sex steroids play the most significant role.¹⁴ Level 2 is local control by factors such as Indian hedgehog (Inh), parathyroid hormone–related peptide (PTHrP), and fibroblast growth factors (FGFs).^14,31 Level 3 is mechanical control.⁴

Systemic Regulation. After birth, GH becomes an important modulator of longitudinal growth and appears to be, together with IGF-1, the central player in the hypothalamus–pituitary–growth plate axis.¹⁴ According to the original somatomedin hypothesis,³² GH stimulates hepatic production of IGF-1, which in turn promotes growth directly at the epiphyseal plate.¹⁷ GH acts on resting zone chondrocytes and is responsible for local IGF-1 production, which stimulates clonal expansion of proliferating chondrocytes in an autocrine/paracrine manner.³³ Infusion of GH or IGF-1 shortens stem- and proliferating-cell cycle times in the growth plate of hypophysectomized rats and decreases the duration of the hypertrophic differentiation phase, with GH being more effective.¹⁷ According to the experimental study of Hunziker and colleagues,³⁴ GH or IGF-1 treatment restores mean cell volume and height, but the growth rate is not normalized by either hormone.

Thyroid hormones also play a vital role in bone growth. T₃ and, to a lesser extent, T₄ are crucial in normal bone maturation.^30,35 Childhood hypothyroidism causes growth failure; growth failure may develop insidiously, but, once established, it is severe.¹⁷ On the other hand, hyperthyroidism increases the growth rate in children but also leads to premature growth plate fusion and short stature.^36,37 T₃ seems to stimulate recruitment of cells from the germinal zone to the proliferating zone and facilitates differentiation of growth plate chondrocytes.^38-40 Its precursor, T₄, increases the number of [³H]methylthymidine-labeled chondrocyte nuclei and [³⁵S]incorporation in Snell dwarf mice growth plates, suggesting a stimulatory role in chondrocyte proliferation and differentiation.⁴¹

Glucocorticoids suppress growth by modifying the GH/IGF-1 pathway at different levels.¹⁷ Silvestrini and colleagues⁴² localized the glucocorticoid receptor in rat bone cells, including chondrocytes. The glucocorticoid receptor was also localized by Abu and colleagues⁴³ in human growth plates, especially in hypertrophic chondrocytes, suggesting direct effects of glucocorticoids on the growth plate. An excess of glucocorticoids enhances bone resorption, inhibits osteoblast activity, and reduces bone matrix production to retard growth in children.^44,45 Excess glucocorticoids also induce apoptosis of osteoblasts and osteocytes in rabbit trabecular bone⁴⁶ and osteoblasts in rat long bones,⁴⁷ resulting in an almost complete absence of new bone formation.¹⁷ In addition, glucocorticoids induce sex hormone deficiency and alter vitamin D metabolism, leading to deleterious effects on growth and skeletal integrity.⁴⁸ Excess glucocorticoids modify the GH/IGF-1 pathway at different levels, suppressing growth.¹⁷ In contrast, low levels of glucocorticoids, as in familial glucocorticoid deficiency, are associated with tall stature.⁴⁹

Longitudinal bone growth is also based on sex hormones, especially during puberty.¹⁷ In rats, estrogen depletion stimulates longitudinal growth, whereas estrogen administration inhibits longitudinal growth.^50-52 Nilsson and colleagues⁵³ studied ovariectomized immature rabbits treated with either estrogen or the selective estrogen receptor modulator raloxifene and found reduced chondrocyte proliferation and growth plate height as well as accelerated growth plate senescence. Many experimental studies have concluded that estrogen can inhibit longitudinal growth in the absence of GH.^51,54,55

Androgens can directly influence growth plate function and may account for some skeletal differences between males and females.^56-58 Unlike estrogens, androgens stimulate longitudinal growth, as shown in several studies that assessed the effect of administering nonaromatizable androgens on longitudinal growth in boys with constitutionally delayed growth.^59,60

Local Regulation. Inh, a master regulator of bone development, coordinates chondrocyte proliferation, chondrocyte differentiation, and osteoblast differentiation.³¹ Inh belongs to the hedgehog protein family, which plays a crucial role in embryonic patterning and development.⁴ The proliferative effect of Inh is likely to be direct action on chondrocytes.³¹ In 1996, Vortkamp and colleagues⁶¹ reported that misexpression of Inh in chicken long bones blocked chondrocyte differentiation. More recently, St-Jacques and colleagues⁶² studied Inh-null mutant mice and found failure of both chondrocyte differentiation and osteoblast development. Inh is now thought to coordinate endochondral ossification, regulating chondrocyte proliferation and differentiation and osteoblast differentiation and coupling chondrogenesis and osteogenesis.^62,63

PTHrP acts primarily to keep proliferating chondrocytes in the proliferative pool.³¹ Mice that did not express PTHrP showed accelerated chondrocyte differentiation leading to dwarfism.⁶⁴ On the other hand, ectopic expression of PTHrP in the growth plate inhibited chondrocyte differentiation, resulting in a smaller cartilaginous skeleton compared with wild-type mice.⁶⁵ PTHrP appears to regulate the rate of programmed chondrocyte differentiation in developing endochondral bone and at the level of the growth plate.^64,66-69

The family of FGFs, which are major regulators of embryonic bone development, has at least 22 members.^70,71 Achondroplasia, the most common type of dwarfism, is caused by an activating mutation in FGF receptor 3 (FGFR3).^72-74 FGF18 deficiency also leads to delayed ossification and decreased expression of osteogenic markers.⁷⁵

Bone morphogenetic proteins (BMPs) are recognized as important regulators of growth, differentiation, and morphogenesis during embryology.⁷⁶ In 2001, Minina and colleagues⁷⁷ showed that normal chondrocyte proliferation requires parallel signaling of both Inh and BMPs and that BMPs can inhibit chondrocyte differentiation independently of the Inh/PTHrP pathway.

Vascular endothelial growth factor (VEGF), a chemoattractant for endothelial cells, is one of the most important growth factors for endothelial cells.⁷⁸ VEGF is a key player in the actions that occur during the end stage of endochondral bone formation; these actions include terminal differentiation of chondrocytes, vascular invasion, chondrocyte apoptosis, and replacement of chondrocytes with bone.^27,79,80 When Gerber and colleagues²⁷ inactivated VEGF in 24-day-old mice, they noticed suppressed blood vessel invasion and trabecular bone formation concomitant with an increased width of the hypertrophic zone.

Mechanical Regulation. Mechanical forces influence bone formation and adaptation.⁸¹ Growth rates from early infancy through late adolescence were found to be strongly correlated between an appropriate measure of mechanical loading (body size, or body weight–bone length) and bone strength (assessed by section modulus).⁸² The observation that compression inhibits bone growth was well known to the ancient Romans.⁸³ In the 19th century, the Hueter-Volkmann law was proclaimed. This law is well known to pediatric orthopedic surgeons and is the basis of growth modulation for correcting angular deformities of the lower extremities and spinal deformities.^4,84

If compression always inhibited bone growth, as it was believed, growth plates would be extremely unstable, as any slight deviation from the straight alignment of the long bones of the lower extremities would induce a vicious circle of positive feedback and result in catastrophic deformities.⁴ Mild compression leads to increased, not decreased, growth. Nevertheless, when compression on one side of the growth plate exceeds a certain level, growth is indeed suppressed, and the lesion begins to worsen.⁴

In 1997, Frost⁸⁵ proposed using a single graph that combines the clinical observation of mechanical forces affecting longitudinal bone growth. Both mild tension and mild compression induce bone growth, whereas heavy compression inhibits growth (Figure 3).

Three rules describe bone adaptation in mathematical terms. First, bone adaptation is driven by dynamic, not static, loading. Second, only a short period of mechanical loading is needed to initiate an adaptive response (extending the loading period has a diminishing effect on further bone adaptation). Third, bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals.⁸¹

Also playing a significant role in bone physiology is the nervous system, with leptin-dependent central control of bone formation via the sympathetic system.⁸⁶ Several investigators have tried to determine the effect of muscle activity on bone growth in length.⁸⁷ Pottorf⁸⁸ in 1916 and Allison and Brooks⁸⁹ in 1921 were among the first to study this correlation; they concluded that long bones grow less after denervation. On the other hand, Ring⁹⁰ in 1961 reported that, despite innervation, longitudinal bone growth was increased. Investigators in more recent studies have advanced the idea that the nervous system plays a negative role in bone physiology. Dysart and colleagues⁸⁷ showed that muscle pull affects periosteal tension and, consequently, bone form and growth in length. In a clinical study involving 32 children with neonatal brachial plexus injury,⁹¹ the ratio of skewness between the affected humeral head and the contralateral normal head was calculated. Skewness was determined by dividing the anterior area of the humeral head by the posterior area. There was a significant preoperative difference between the 2 sides, but the skewness ratio was significantly improved after surgery.

Bone Growth in Width

Bone growth in width has not received as much attention as longitudinal bone growth. Several studies have indicated that body mass and muscle strength have important influences on long bone strength in children and adolescents.^92-97 As bone width changes only slowly after the growth period, bone growth in width is one of the most important determinants of bone strength throughout life.⁴ It is clear that, if bones grew in length without increasing in width, they would become unstable and break.⁴

Histologically, osteoblasts add mineralized tissue to the outer (periosteal) bone surface. This process is periosteal apposition.⁹⁸ The periosteum has an outer layer, composed mainly of fibrous tissue, and an inner layer, the cambium, which harbors osteogenic cells.⁴ In children, bone formation is continuous, which is the hallmark of modeling^99,100; in adults, periosteal bone may undergo cyclical resorption and formation, which are characteristic of remodeling.^101,102

Macroscopically, bone grows rapidly during early life; then, growth continuously slows down until reaching a nadir during early school age.⁴ It is clear that wider bones must have higher midshaft periosteal apposition rates, as this is how they become wider.^4,103

Regulation of Bone Growth in Width (Table)

Systemic Regulation. Periosteal apposition at diaphyseal bone sites is stimulated by androgen and GH and inhibited by estrogens.^104-106 In an experimental study, Turner and colleagues¹⁰⁴ found that androgen treatment stimulated bone formation in orchiectomized rats and suppressed bone formation in ovariectomized rats. A large dose of diethylstilbestrol also suppressed bone formation in ovariectomized rats. Parathyroid hormone is associated with faster periosteal expansion in adults, according to Parfitt.¹⁰⁷ In addition, nutrition with high calcium intake has the same effects on children, especially those with high levels of physical activity.¹⁰⁸

Local Regulation. Given that periosteal bone development is site-specific, whereas systemic hormones and nutrition are blind to structure,⁴ it is clear that local regulation is key to bone growth in width. Genetic heritage seems to have an overwhelming effect on periosteal bone development. Volkman and colleagues,¹⁰⁹ who experimented with various genetic markers in rats, concluded that genetic control of cortical bone geometry is complex and that femoral size and shape may be influenced by different but overlapping groups of polymorphic loci.

Mechanical Regulation. Mechanical forces seem to be very important in determining bone width. For example, the difference in width between femur and humerus can be explained by the different mechanical forces acting on each bone. This perspective is supported by Ruff,⁸² who showed that the correlation of body size (body weight–bone length) and bone strength is stronger in the femur than in the humerus.

The vital role of mechanical forces in bone growth in width is also supported by results of a study by Goodship and colleagues,¹¹⁰ who overloaded the radius of young pigs by partially removing the ulna. They showed that the radius was strengthened by rapid periosteal apposition. This effect has also been noticed in the clinical setting, when the tibia is replaced with the fibula, which quickly hypertrophies in order to resemble the tibia.¹¹¹

Conclusion

Longitudinal bone growth has been extensively studied. Systemic and local hormonal pathways control bone growth in a complicated regulation system. Mechanical loading is also strongly correlated with longitudinal bone growth. Bone growth in width has received less attention. Despite its importance in bone stability, periosteal development—and periosteal apposition and resorption more specifically—has not received enough attention. Researchers need to clarify the role of genetic factors affecting periosteal development.

Differences in bone size are established early in life, before puberty and perhaps even in utero.¹ Bone begins to form when mesenchymal cells form condensations—clusters of cells that adhere through expression of adhesion molecules² (Figure 1). Bone must be stiff, flexible enough to change shape to absorb energy, and light enough to allow mobility.^1,3 Longitudinal bone growth is detrimental to bone stability, but this effect is counteracted by concomitant bone growth in width.⁴ Bone growth in width has not been studied as extensively, despite its paramount role in skeletal development.⁵

Bone growth and development are products of the complex interactions of genetic and environmental factors, including diet, hormones, and mechanical stimuli.^6-9 Longitudinal bone growth is controlled by systemic and local hormones and local mechanical factors. Two models for control of bone growth in width have been suggested—the mechanostat theory (mechanical requirements regulate periosteal apposition) and the sizostat hypothesis (a master gene or set of genes regulates bone growth in width so bone reaches a preprogrammed size, independent of mechanical requirements).⁵

In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases¹⁰ and fracture risk.^11,12

Growth Plate

The growth plate consists mainly of collagen fibrils, proteoglycans, and water, arranged to form a sort of sponge with very small pores.¹³ The growth plate is located between epiphyseal and metaphyseal bone at the distal end of long bones¹⁴ and is strain-rate–dependent,^15,16 which means it is hard when squeezed rapidly but soft when deformed slowly. The growth plate becomes ossified after puberty and epiphyseal fusion.¹⁷

Histologically, the growth plate consists of horizontal zones of chondrocytes at different stages of differentiation.⁴ The germinal zone, at the epiphyseal end of the growth plate, contains resting chondrocytes, which seem crucial in orienting the underlying columns of chondrocytes and, therefore, in unidirectional bone growth, probably by secretion of a growth plate–orienting factor.^14,18 Next is the proliferative zone, a matrix-rich zone in which flattened chondrocytes undergo longitudinal cell division and orient themselves in typical column-wise fashion. At some point, proliferating chondrocytes lose their capacity to divide; they start to differentiate and become prehypertrophic, coinciding with a size increase.⁴ Proliferating chondrocytes are located in the transition (maturation or prehypertrophic) zone. In the hypertrophic zone, round chondrocytes secrete matrix proteins in large amounts.¹⁴ This stage is characterized by an increase in intracellular calcium concentration, which is essential in the production of matrix vesicles. These vesicles, small membrane-enclosed particles, are released from chondrocytes^19,20 and secrete calcium phosphates, hydroxyapatite, and matrix metalloproteinases, resulting in mineralization of the vesicles and their surrounding matrix.⁴ The chondrocytes in this mineralized zone eventually undergo programmed cell death (apoptosis), leaving a scaffold for new bone formation.

Longitudinal Bone Growth

Generally, bones increase in length as long as new material is being squeezed between the reserve zone of the growth plate and the zone of provisional calcification.⁴

Postnatal linear growth occurs in 3 phases. Phase 1 is characterized by a high rate of growth at the beginning of fetal life, and then rapid deceleration up to about 3 years; phase 2, by a lower, slowly decelerating growth rate up to puberty; and phase 3, by an increased rate of longitudinal growth until a peak is reached.^14,21,22

In 1964, Park²³ proposed that the structure of the epiphyseal cartilage may determine the pattern of the growing bone shaft. The changes within the hypertrophic zone are directly related to matrix mineralization, vascular invasion, and subsequent development.²⁴ Intracellular calcium concentration increases in the hypertrophic chondrocytes in the hypertrophic zone of growth plate cartilage; at some point, these chondrocytes begin to mineralize the longitudinal septa in the surrounding matrix²⁵ (Figure 2). At the growth cartilage junction, mononuclear cells of undetermined origin resorb the unmineralized horizontal septa of the growth cartilage. These cells are called septoclasts or chondroclasts.^25,26 Blood vessels invade the area and pave the way for bone cell precursors.²⁷ Eighty percent of the longitudinal septa of the growth cartilage is rapidly resorbed in the metaphyseal zone immediately behind the invading blood vessels, paving the way for bone cell precursors.²⁸ Fazzalari and colleagues²⁸ reported that about 40% of mineralized septa serves as scaffold for the formation of primary bone trabeculae; the other 60% is absorbed by chondroclasts (osteoclasts) near the vascular invasion front.

Regulation of Longitudinal Bone Growth

Longitudinal bone growth is regulated by genetic, hormonal, growth, and environment factors^17,29-31 (Table). It must be controlled on at least 3 different levels.⁴ Level 1 is systemic control by factors such as growth hormone (GH), sex hormones, and glucocorticoids. The major systemic hormones that control longitudinal bone growth during childhood are GH, insulin-like growth factor 1 (IGF-1), the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄), and glucocorticoids; during puberty, the sex steroids play the most significant role.¹⁴ Level 2 is local control by factors such as Indian hedgehog (Inh), parathyroid hormone–related peptide (PTHrP), and fibroblast growth factors (FGFs).^14,31 Level 3 is mechanical control.⁴

Systemic Regulation. After birth, GH becomes an important modulator of longitudinal growth and appears to be, together with IGF-1, the central player in the hypothalamus–pituitary–growth plate axis.¹⁴ According to the original somatomedin hypothesis,³² GH stimulates hepatic production of IGF-1, which in turn promotes growth directly at the epiphyseal plate.¹⁷ GH acts on resting zone chondrocytes and is responsible for local IGF-1 production, which stimulates clonal expansion of proliferating chondrocytes in an autocrine/paracrine manner.³³ Infusion of GH or IGF-1 shortens stem- and proliferating-cell cycle times in the growth plate of hypophysectomized rats and decreases the duration of the hypertrophic differentiation phase, with GH being more effective.¹⁷ According to the experimental study of Hunziker and colleagues,³⁴ GH or IGF-1 treatment restores mean cell volume and height, but the growth rate is not normalized by either hormone.

Thyroid hormones also play a vital role in bone growth. T₃ and, to a lesser extent, T₄ are crucial in normal bone maturation.^30,35 Childhood hypothyroidism causes growth failure; growth failure may develop insidiously, but, once established, it is severe.¹⁷ On the other hand, hyperthyroidism increases the growth rate in children but also leads to premature growth plate fusion and short stature.^36,37 T₃ seems to stimulate recruitment of cells from the germinal zone to the proliferating zone and facilitates differentiation of growth plate chondrocytes.^38-40 Its precursor, T₄, increases the number of [³H]methylthymidine-labeled chondrocyte nuclei and [³⁵S]incorporation in Snell dwarf mice growth plates, suggesting a stimulatory role in chondrocyte proliferation and differentiation.⁴¹

Glucocorticoids suppress growth by modifying the GH/IGF-1 pathway at different levels.¹⁷ Silvestrini and colleagues⁴² localized the glucocorticoid receptor in rat bone cells, including chondrocytes. The glucocorticoid receptor was also localized by Abu and colleagues⁴³ in human growth plates, especially in hypertrophic chondrocytes, suggesting direct effects of glucocorticoids on the growth plate. An excess of glucocorticoids enhances bone resorption, inhibits osteoblast activity, and reduces bone matrix production to retard growth in children.^44,45 Excess glucocorticoids also induce apoptosis of osteoblasts and osteocytes in rabbit trabecular bone⁴⁶ and osteoblasts in rat long bones,⁴⁷ resulting in an almost complete absence of new bone formation.¹⁷ In addition, glucocorticoids induce sex hormone deficiency and alter vitamin D metabolism, leading to deleterious effects on growth and skeletal integrity.⁴⁸ Excess glucocorticoids modify the GH/IGF-1 pathway at different levels, suppressing growth.¹⁷ In contrast, low levels of glucocorticoids, as in familial glucocorticoid deficiency, are associated with tall stature.⁴⁹

Longitudinal bone growth is also based on sex hormones, especially during puberty.¹⁷ In rats, estrogen depletion stimulates longitudinal growth, whereas estrogen administration inhibits longitudinal growth.^50-52 Nilsson and colleagues⁵³ studied ovariectomized immature rabbits treated with either estrogen or the selective estrogen receptor modulator raloxifene and found reduced chondrocyte proliferation and growth plate height as well as accelerated growth plate senescence. Many experimental studies have concluded that estrogen can inhibit longitudinal growth in the absence of GH.^51,54,55

Androgens can directly influence growth plate function and may account for some skeletal differences between males and females.^56-58 Unlike estrogens, androgens stimulate longitudinal growth, as shown in several studies that assessed the effect of administering nonaromatizable androgens on longitudinal growth in boys with constitutionally delayed growth.^59,60

Local Regulation. Inh, a master regulator of bone development, coordinates chondrocyte proliferation, chondrocyte differentiation, and osteoblast differentiation.³¹ Inh belongs to the hedgehog protein family, which plays a crucial role in embryonic patterning and development.⁴ The proliferative effect of Inh is likely to be direct action on chondrocytes.³¹ In 1996, Vortkamp and colleagues⁶¹ reported that misexpression of Inh in chicken long bones blocked chondrocyte differentiation. More recently, St-Jacques and colleagues⁶² studied Inh-null mutant mice and found failure of both chondrocyte differentiation and osteoblast development. Inh is now thought to coordinate endochondral ossification, regulating chondrocyte proliferation and differentiation and osteoblast differentiation and coupling chondrogenesis and osteogenesis.^62,63

PTHrP acts primarily to keep proliferating chondrocytes in the proliferative pool.³¹ Mice that did not express PTHrP showed accelerated chondrocyte differentiation leading to dwarfism.⁶⁴ On the other hand, ectopic expression of PTHrP in the growth plate inhibited chondrocyte differentiation, resulting in a smaller cartilaginous skeleton compared with wild-type mice.⁶⁵ PTHrP appears to regulate the rate of programmed chondrocyte differentiation in developing endochondral bone and at the level of the growth plate.^64,66-69

The family of FGFs, which are major regulators of embryonic bone development, has at least 22 members.^70,71 Achondroplasia, the most common type of dwarfism, is caused by an activating mutation in FGF receptor 3 (FGFR3).^72-74 FGF18 deficiency also leads to delayed ossification and decreased expression of osteogenic markers.⁷⁵

Bone morphogenetic proteins (BMPs) are recognized as important regulators of growth, differentiation, and morphogenesis during embryology.⁷⁶ In 2001, Minina and colleagues⁷⁷ showed that normal chondrocyte proliferation requires parallel signaling of both Inh and BMPs and that BMPs can inhibit chondrocyte differentiation independently of the Inh/PTHrP pathway.

Vascular endothelial growth factor (VEGF), a chemoattractant for endothelial cells, is one of the most important growth factors for endothelial cells.⁷⁸ VEGF is a key player in the actions that occur during the end stage of endochondral bone formation; these actions include terminal differentiation of chondrocytes, vascular invasion, chondrocyte apoptosis, and replacement of chondrocytes with bone.^27,79,80 When Gerber and colleagues²⁷ inactivated VEGF in 24-day-old mice, they noticed suppressed blood vessel invasion and trabecular bone formation concomitant with an increased width of the hypertrophic zone.

Mechanical Regulation. Mechanical forces influence bone formation and adaptation.⁸¹ Growth rates from early infancy through late adolescence were found to be strongly correlated between an appropriate measure of mechanical loading (body size, or body weight–bone length) and bone strength (assessed by section modulus).⁸² The observation that compression inhibits bone growth was well known to the ancient Romans.⁸³ In the 19th century, the Hueter-Volkmann law was proclaimed. This law is well known to pediatric orthopedic surgeons and is the basis of growth modulation for correcting angular deformities of the lower extremities and spinal deformities.^4,84

If compression always inhibited bone growth, as it was believed, growth plates would be extremely unstable, as any slight deviation from the straight alignment of the long bones of the lower extremities would induce a vicious circle of positive feedback and result in catastrophic deformities.⁴ Mild compression leads to increased, not decreased, growth. Nevertheless, when compression on one side of the growth plate exceeds a certain level, growth is indeed suppressed, and the lesion begins to worsen.⁴

In 1997, Frost⁸⁵ proposed using a single graph that combines the clinical observation of mechanical forces affecting longitudinal bone growth. Both mild tension and mild compression induce bone growth, whereas heavy compression inhibits growth (Figure 3).

Three rules describe bone adaptation in mathematical terms. First, bone adaptation is driven by dynamic, not static, loading. Second, only a short period of mechanical loading is needed to initiate an adaptive response (extending the loading period has a diminishing effect on further bone adaptation). Third, bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals.⁸¹

Also playing a significant role in bone physiology is the nervous system, with leptin-dependent central control of bone formation via the sympathetic system.⁸⁶ Several investigators have tried to determine the effect of muscle activity on bone growth in length.⁸⁷ Pottorf⁸⁸ in 1916 and Allison and Brooks⁸⁹ in 1921 were among the first to study this correlation; they concluded that long bones grow less after denervation. On the other hand, Ring⁹⁰ in 1961 reported that, despite innervation, longitudinal bone growth was increased. Investigators in more recent studies have advanced the idea that the nervous system plays a negative role in bone physiology. Dysart and colleagues⁸⁷ showed that muscle pull affects periosteal tension and, consequently, bone form and growth in length. In a clinical study involving 32 children with neonatal brachial plexus injury,⁹¹ the ratio of skewness between the affected humeral head and the contralateral normal head was calculated. Skewness was determined by dividing the anterior area of the humeral head by the posterior area. There was a significant preoperative difference between the 2 sides, but the skewness ratio was significantly improved after surgery.

Bone Growth in Width

Bone growth in width has not received as much attention as longitudinal bone growth. Several studies have indicated that body mass and muscle strength have important influences on long bone strength in children and adolescents.^92-97 As bone width changes only slowly after the growth period, bone growth in width is one of the most important determinants of bone strength throughout life.⁴ It is clear that, if bones grew in length without increasing in width, they would become unstable and break.⁴

Histologically, osteoblasts add mineralized tissue to the outer (periosteal) bone surface. This process is periosteal apposition.⁹⁸ The periosteum has an outer layer, composed mainly of fibrous tissue, and an inner layer, the cambium, which harbors osteogenic cells.⁴ In children, bone formation is continuous, which is the hallmark of modeling^99,100; in adults, periosteal bone may undergo cyclical resorption and formation, which are characteristic of remodeling.^101,102

Macroscopically, bone grows rapidly during early life; then, growth continuously slows down until reaching a nadir during early school age.⁴ It is clear that wider bones must have higher midshaft periosteal apposition rates, as this is how they become wider.^4,103

Regulation of Bone Growth in Width (Table)

Systemic Regulation. Periosteal apposition at diaphyseal bone sites is stimulated by androgen and GH and inhibited by estrogens.^104-106 In an experimental study, Turner and colleagues¹⁰⁴ found that androgen treatment stimulated bone formation in orchiectomized rats and suppressed bone formation in ovariectomized rats. A large dose of diethylstilbestrol also suppressed bone formation in ovariectomized rats. Parathyroid hormone is associated with faster periosteal expansion in adults, according to Parfitt.¹⁰⁷ In addition, nutrition with high calcium intake has the same effects on children, especially those with high levels of physical activity.¹⁰⁸

Local Regulation. Given that periosteal bone development is site-specific, whereas systemic hormones and nutrition are blind to structure,⁴ it is clear that local regulation is key to bone growth in width. Genetic heritage seems to have an overwhelming effect on periosteal bone development. Volkman and colleagues,¹⁰⁹ who experimented with various genetic markers in rats, concluded that genetic control of cortical bone geometry is complex and that femoral size and shape may be influenced by different but overlapping groups of polymorphic loci.

Mechanical Regulation. Mechanical forces seem to be very important in determining bone width. For example, the difference in width between femur and humerus can be explained by the different mechanical forces acting on each bone. This perspective is supported by Ruff,⁸² who showed that the correlation of body size (body weight–bone length) and bone strength is stronger in the femur than in the humerus.

The vital role of mechanical forces in bone growth in width is also supported by results of a study by Goodship and colleagues,¹¹⁰ who overloaded the radius of young pigs by partially removing the ulna. They showed that the radius was strengthened by rapid periosteal apposition. This effect has also been noticed in the clinical setting, when the tibia is replaced with the fibula, which quickly hypertrophies in order to resemble the tibia.¹¹¹

Conclusion

Longitudinal bone growth has been extensively studied. Systemic and local hormonal pathways control bone growth in a complicated regulation system. Mechanical loading is also strongly correlated with longitudinal bone growth. Bone growth in width has received less attention. Despite its importance in bone stability, periosteal development—and periosteal apposition and resorption more specifically—has not received enough attention. Researchers need to clarify the role of genetic factors affecting periosteal development.

Differences in bone size are established early in life, before puberty and perhaps even in utero.¹ Bone begins to form when mesenchymal cells form condensations—clusters of cells that adhere through expression of adhesion molecules² (Figure 1). Bone must be stiff, flexible enough to change shape to absorb energy, and light enough to allow mobility.^1,3 Longitudinal bone growth is detrimental to bone stability, but this effect is counteracted by concomitant bone growth in width.⁴ Bone growth in width has not been studied as extensively, despite its paramount role in skeletal development.⁵

Bone growth and development are products of the complex interactions of genetic and environmental factors, including diet, hormones, and mechanical stimuli.^6-9 Longitudinal bone growth is controlled by systemic and local hormones and local mechanical factors. Two models for control of bone growth in width have been suggested—the mechanostat theory (mechanical requirements regulate periosteal apposition) and the sizostat hypothesis (a master gene or set of genes regulates bone growth in width so bone reaches a preprogrammed size, independent of mechanical requirements).⁵

In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases¹⁰ and fracture risk.^11,12

Growth Plate

The growth plate consists mainly of collagen fibrils, proteoglycans, and water, arranged to form a sort of sponge with very small pores.¹³ The growth plate is located between epiphyseal and metaphyseal bone at the distal end of long bones¹⁴ and is strain-rate–dependent,^15,16 which means it is hard when squeezed rapidly but soft when deformed slowly. The growth plate becomes ossified after puberty and epiphyseal fusion.¹⁷

Histologically, the growth plate consists of horizontal zones of chondrocytes at different stages of differentiation.⁴ The germinal zone, at the epiphyseal end of the growth plate, contains resting chondrocytes, which seem crucial in orienting the underlying columns of chondrocytes and, therefore, in unidirectional bone growth, probably by secretion of a growth plate–orienting factor.^14,18 Next is the proliferative zone, a matrix-rich zone in which flattened chondrocytes undergo longitudinal cell division and orient themselves in typical column-wise fashion. At some point, proliferating chondrocytes lose their capacity to divide; they start to differentiate and become prehypertrophic, coinciding with a size increase.⁴ Proliferating chondrocytes are located in the transition (maturation or prehypertrophic) zone. In the hypertrophic zone, round chondrocytes secrete matrix proteins in large amounts.¹⁴ This stage is characterized by an increase in intracellular calcium concentration, which is essential in the production of matrix vesicles. These vesicles, small membrane-enclosed particles, are released from chondrocytes^19,20 and secrete calcium phosphates, hydroxyapatite, and matrix metalloproteinases, resulting in mineralization of the vesicles and their surrounding matrix.⁴ The chondrocytes in this mineralized zone eventually undergo programmed cell death (apoptosis), leaving a scaffold for new bone formation.

Longitudinal Bone Growth

Generally, bones increase in length as long as new material is being squeezed between the reserve zone of the growth plate and the zone of provisional calcification.⁴

Postnatal linear growth occurs in 3 phases. Phase 1 is characterized by a high rate of growth at the beginning of fetal life, and then rapid deceleration up to about 3 years; phase 2, by a lower, slowly decelerating growth rate up to puberty; and phase 3, by an increased rate of longitudinal growth until a peak is reached.^14,21,22

In 1964, Park²³ proposed that the structure of the epiphyseal cartilage may determine the pattern of the growing bone shaft. The changes within the hypertrophic zone are directly related to matrix mineralization, vascular invasion, and subsequent development.²⁴ Intracellular calcium concentration increases in the hypertrophic chondrocytes in the hypertrophic zone of growth plate cartilage; at some point, these chondrocytes begin to mineralize the longitudinal septa in the surrounding matrix²⁵ (Figure 2). At the growth cartilage junction, mononuclear cells of undetermined origin resorb the unmineralized horizontal septa of the growth cartilage. These cells are called septoclasts or chondroclasts.^25,26 Blood vessels invade the area and pave the way for bone cell precursors.²⁷ Eighty percent of the longitudinal septa of the growth cartilage is rapidly resorbed in the metaphyseal zone immediately behind the invading blood vessels, paving the way for bone cell precursors.²⁸ Fazzalari and colleagues²⁸ reported that about 40% of mineralized septa serves as scaffold for the formation of primary bone trabeculae; the other 60% is absorbed by chondroclasts (osteoclasts) near the vascular invasion front.

Regulation of Longitudinal Bone Growth

Longitudinal bone growth is regulated by genetic, hormonal, growth, and environment factors^17,29-31 (Table). It must be controlled on at least 3 different levels.⁴ Level 1 is systemic control by factors such as growth hormone (GH), sex hormones, and glucocorticoids. The major systemic hormones that control longitudinal bone growth during childhood are GH, insulin-like growth factor 1 (IGF-1), the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄), and glucocorticoids; during puberty, the sex steroids play the most significant role.¹⁴ Level 2 is local control by factors such as Indian hedgehog (Inh), parathyroid hormone–related peptide (PTHrP), and fibroblast growth factors (FGFs).^14,31 Level 3 is mechanical control.⁴

Systemic Regulation. After birth, GH becomes an important modulator of longitudinal growth and appears to be, together with IGF-1, the central player in the hypothalamus–pituitary–growth plate axis.¹⁴ According to the original somatomedin hypothesis,³² GH stimulates hepatic production of IGF-1, which in turn promotes growth directly at the epiphyseal plate.¹⁷ GH acts on resting zone chondrocytes and is responsible for local IGF-1 production, which stimulates clonal expansion of proliferating chondrocytes in an autocrine/paracrine manner.³³ Infusion of GH or IGF-1 shortens stem- and proliferating-cell cycle times in the growth plate of hypophysectomized rats and decreases the duration of the hypertrophic differentiation phase, with GH being more effective.¹⁷ According to the experimental study of Hunziker and colleagues,³⁴ GH or IGF-1 treatment restores mean cell volume and height, but the growth rate is not normalized by either hormone.

Thyroid hormones also play a vital role in bone growth. T₃ and, to a lesser extent, T₄ are crucial in normal bone maturation.^30,35 Childhood hypothyroidism causes growth failure; growth failure may develop insidiously, but, once established, it is severe.¹⁷ On the other hand, hyperthyroidism increases the growth rate in children but also leads to premature growth plate fusion and short stature.^36,37 T₃ seems to stimulate recruitment of cells from the germinal zone to the proliferating zone and facilitates differentiation of growth plate chondrocytes.^38-40 Its precursor, T₄, increases the number of [³H]methylthymidine-labeled chondrocyte nuclei and [³⁵S]incorporation in Snell dwarf mice growth plates, suggesting a stimulatory role in chondrocyte proliferation and differentiation.⁴¹

Glucocorticoids suppress growth by modifying the GH/IGF-1 pathway at different levels.¹⁷ Silvestrini and colleagues⁴² localized the glucocorticoid receptor in rat bone cells, including chondrocytes. The glucocorticoid receptor was also localized by Abu and colleagues⁴³ in human growth plates, especially in hypertrophic chondrocytes, suggesting direct effects of glucocorticoids on the growth plate. An excess of glucocorticoids enhances bone resorption, inhibits osteoblast activity, and reduces bone matrix production to retard growth in children.^44,45 Excess glucocorticoids also induce apoptosis of osteoblasts and osteocytes in rabbit trabecular bone⁴⁶ and osteoblasts in rat long bones,⁴⁷ resulting in an almost complete absence of new bone formation.¹⁷ In addition, glucocorticoids induce sex hormone deficiency and alter vitamin D metabolism, leading to deleterious effects on growth and skeletal integrity.⁴⁸ Excess glucocorticoids modify the GH/IGF-1 pathway at different levels, suppressing growth.¹⁷ In contrast, low levels of glucocorticoids, as in familial glucocorticoid deficiency, are associated with tall stature.⁴⁹

Longitudinal bone growth is also based on sex hormones, especially during puberty.¹⁷ In rats, estrogen depletion stimulates longitudinal growth, whereas estrogen administration inhibits longitudinal growth.^50-52 Nilsson and colleagues⁵³ studied ovariectomized immature rabbits treated with either estrogen or the selective estrogen receptor modulator raloxifene and found reduced chondrocyte proliferation and growth plate height as well as accelerated growth plate senescence. Many experimental studies have concluded that estrogen can inhibit longitudinal growth in the absence of GH.^51,54,55

Androgens can directly influence growth plate function and may account for some skeletal differences between males and females.^56-58 Unlike estrogens, androgens stimulate longitudinal growth, as shown in several studies that assessed the effect of administering nonaromatizable androgens on longitudinal growth in boys with constitutionally delayed growth.^59,60

Local Regulation. Inh, a master regulator of bone development, coordinates chondrocyte proliferation, chondrocyte differentiation, and osteoblast differentiation.³¹ Inh belongs to the hedgehog protein family, which plays a crucial role in embryonic patterning and development.⁴ The proliferative effect of Inh is likely to be direct action on chondrocytes.³¹ In 1996, Vortkamp and colleagues⁶¹ reported that misexpression of Inh in chicken long bones blocked chondrocyte differentiation. More recently, St-Jacques and colleagues⁶² studied Inh-null mutant mice and found failure of both chondrocyte differentiation and osteoblast development. Inh is now thought to coordinate endochondral ossification, regulating chondrocyte proliferation and differentiation and osteoblast differentiation and coupling chondrogenesis and osteogenesis.^62,63

PTHrP acts primarily to keep proliferating chondrocytes in the proliferative pool.³¹ Mice that did not express PTHrP showed accelerated chondrocyte differentiation leading to dwarfism.⁶⁴ On the other hand, ectopic expression of PTHrP in the growth plate inhibited chondrocyte differentiation, resulting in a smaller cartilaginous skeleton compared with wild-type mice.⁶⁵ PTHrP appears to regulate the rate of programmed chondrocyte differentiation in developing endochondral bone and at the level of the growth plate.^64,66-69

The family of FGFs, which are major regulators of embryonic bone development, has at least 22 members.^70,71 Achondroplasia, the most common type of dwarfism, is caused by an activating mutation in FGF receptor 3 (FGFR3).^72-74 FGF18 deficiency also leads to delayed ossification and decreased expression of osteogenic markers.⁷⁵

Bone morphogenetic proteins (BMPs) are recognized as important regulators of growth, differentiation, and morphogenesis during embryology.⁷⁶ In 2001, Minina and colleagues⁷⁷ showed that normal chondrocyte proliferation requires parallel signaling of both Inh and BMPs and that BMPs can inhibit chondrocyte differentiation independently of the Inh/PTHrP pathway.

Vascular endothelial growth factor (VEGF), a chemoattractant for endothelial cells, is one of the most important growth factors for endothelial cells.⁷⁸ VEGF is a key player in the actions that occur during the end stage of endochondral bone formation; these actions include terminal differentiation of chondrocytes, vascular invasion, chondrocyte apoptosis, and replacement of chondrocytes with bone.^27,79,80 When Gerber and colleagues²⁷ inactivated VEGF in 24-day-old mice, they noticed suppressed blood vessel invasion and trabecular bone formation concomitant with an increased width of the hypertrophic zone.

Mechanical Regulation. Mechanical forces influence bone formation and adaptation.⁸¹ Growth rates from early infancy through late adolescence were found to be strongly correlated between an appropriate measure of mechanical loading (body size, or body weight–bone length) and bone strength (assessed by section modulus).⁸² The observation that compression inhibits bone growth was well known to the ancient Romans.⁸³ In the 19th century, the Hueter-Volkmann law was proclaimed. This law is well known to pediatric orthopedic surgeons and is the basis of growth modulation for correcting angular deformities of the lower extremities and spinal deformities.^4,84

If compression always inhibited bone growth, as it was believed, growth plates would be extremely unstable, as any slight deviation from the straight alignment of the long bones of the lower extremities would induce a vicious circle of positive feedback and result in catastrophic deformities.⁴ Mild compression leads to increased, not decreased, growth. Nevertheless, when compression on one side of the growth plate exceeds a certain level, growth is indeed suppressed, and the lesion begins to worsen.⁴

In 1997, Frost⁸⁵ proposed using a single graph that combines the clinical observation of mechanical forces affecting longitudinal bone growth. Both mild tension and mild compression induce bone growth, whereas heavy compression inhibits growth (Figure 3).

Three rules describe bone adaptation in mathematical terms. First, bone adaptation is driven by dynamic, not static, loading. Second, only a short period of mechanical loading is needed to initiate an adaptive response (extending the loading period has a diminishing effect on further bone adaptation). Third, bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals.⁸¹

Also playing a significant role in bone physiology is the nervous system, with leptin-dependent central control of bone formation via the sympathetic system.⁸⁶ Several investigators have tried to determine the effect of muscle activity on bone growth in length.⁸⁷ Pottorf⁸⁸ in 1916 and Allison and Brooks⁸⁹ in 1921 were among the first to study this correlation; they concluded that long bones grow less after denervation. On the other hand, Ring⁹⁰ in 1961 reported that, despite innervation, longitudinal bone growth was increased. Investigators in more recent studies have advanced the idea that the nervous system plays a negative role in bone physiology. Dysart and colleagues⁸⁷ showed that muscle pull affects periosteal tension and, consequently, bone form and growth in length. In a clinical study involving 32 children with neonatal brachial plexus injury,⁹¹ the ratio of skewness between the affected humeral head and the contralateral normal head was calculated. Skewness was determined by dividing the anterior area of the humeral head by the posterior area. There was a significant preoperative difference between the 2 sides, but the skewness ratio was significantly improved after surgery.

Bone Growth in Width

Bone growth in width has not received as much attention as longitudinal bone growth. Several studies have indicated that body mass and muscle strength have important influences on long bone strength in children and adolescents.^92-97 As bone width changes only slowly after the growth period, bone growth in width is one of the most important determinants of bone strength throughout life.⁴ It is clear that, if bones grew in length without increasing in width, they would become unstable and break.⁴

Histologically, osteoblasts add mineralized tissue to the outer (periosteal) bone surface. This process is periosteal apposition.⁹⁸ The periosteum has an outer layer, composed mainly of fibrous tissue, and an inner layer, the cambium, which harbors osteogenic cells.⁴ In children, bone formation is continuous, which is the hallmark of modeling^99,100; in adults, periosteal bone may undergo cyclical resorption and formation, which are characteristic of remodeling.^101,102

Macroscopically, bone grows rapidly during early life; then, growth continuously slows down until reaching a nadir during early school age.⁴ It is clear that wider bones must have higher midshaft periosteal apposition rates, as this is how they become wider.^4,103

Regulation of Bone Growth in Width (Table)

Systemic Regulation. Periosteal apposition at diaphyseal bone sites is stimulated by androgen and GH and inhibited by estrogens.^104-106 In an experimental study, Turner and colleagues¹⁰⁴ found that androgen treatment stimulated bone formation in orchiectomized rats and suppressed bone formation in ovariectomized rats. A large dose of diethylstilbestrol also suppressed bone formation in ovariectomized rats. Parathyroid hormone is associated with faster periosteal expansion in adults, according to Parfitt.¹⁰⁷ In addition, nutrition with high calcium intake has the same effects on children, especially those with high levels of physical activity.¹⁰⁸

Local Regulation. Given that periosteal bone development is site-specific, whereas systemic hormones and nutrition are blind to structure,⁴ it is clear that local regulation is key to bone growth in width. Genetic heritage seems to have an overwhelming effect on periosteal bone development. Volkman and colleagues,¹⁰⁹ who experimented with various genetic markers in rats, concluded that genetic control of cortical bone geometry is complex and that femoral size and shape may be influenced by different but overlapping groups of polymorphic loci.

Mechanical Regulation. Mechanical forces seem to be very important in determining bone width. For example, the difference in width between femur and humerus can be explained by the different mechanical forces acting on each bone. This perspective is supported by Ruff,⁸² who showed that the correlation of body size (body weight–bone length) and bone strength is stronger in the femur than in the humerus.

The vital role of mechanical forces in bone growth in width is also supported by results of a study by Goodship and colleagues,¹¹⁰ who overloaded the radius of young pigs by partially removing the ulna. They showed that the radius was strengthened by rapid periosteal apposition. This effect has also been noticed in the clinical setting, when the tibia is replaced with the fibula, which quickly hypertrophies in order to resemble the tibia.¹¹¹

Conclusion

Longitudinal bone growth has been extensively studied. Systemic and local hormonal pathways control bone growth in a complicated regulation system. Mechanical loading is also strongly correlated with longitudinal bone growth. Bone growth in width has received less attention. Despite its importance in bone stability, periosteal development—and periosteal apposition and resorption more specifically—has not received enough attention. Researchers need to clarify the role of genetic factors affecting periosteal development.

Over the past year, much attention has been devoted to labor curves. Is the original Friedman labor curve, which dates to the 1950s, still applicable today? Or do contemporary women labor differently? And if we update our approach to labor management, can we reduce the rate of primary cesarean?

In this Update, we explore these questions, as well as two others:

Is adherence to new labor curves the best way to reduce the rate of primary cesarean?

American College of Obstetricians and Gynecologists. Obstetric Care Consensus No. 1: Safe prevention of the primary cesarean delivery. Obstet Gynecol. 2014;123(3):693–711.

Cohen WR, Friedman EA. Perils of the new labor management guidelines [published online ahead of print September 16, 2014]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2014.09.008.

In 2012, the cesarean delivery rate in the United States remained at 32.8%, a high percentage when one considers the increased risks that major abdominal surgery poses in both the short and long term (blood loss, transfusion, infection, venous thromboembolism, abnormal placentation, hysterectomy).¹ The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have made it a priority to reduce the cesarean delivery rate, focusing their efforts on the primary cesarean. In March 2014, they jointly issued guidelines on the “Safe prevention of the primary cesarean delivery,” highlighting labor dystocia as a top cause.

When contemporary data from the Consortium on Safe Labor were applied to the original Friedman labor curve, investigators found that the active phase of labor may be slower than previously thought.² The maximum slope for the rate of cervical change was not observed until 6 cm of dilation. This finding potentially changes the point at which arrest of the active phase may be declared. The maximum duration of augmentation with oxytocin also has been extended, based on studies that demonstrated increased vaginal delivery rates.

The Consortium on Safe Labor proposed that, by subjecting a contemporary population to decades-old standards, we have been intervening with primary cesarean too early in the treatment of labor dystocia.

What the guidelines say
The new recommendations from ACOG-SMFM suggest that arrest of the active phase of labor can be declared only when the patient is dilated at least 6 cm with ruptured membranes after either 4 hours of adequate uterine contractions or at least 6 hours of oxytocin administration with inadequate uterine contractions or no cervical change.

Although the recommendations state that there is no maximum duration of the second stage of labor, we may increase the vaginal delivery rate by increasing the duration of pushing to 2 hours for a multiparous patient and 3 hours for a nulliparous patient (with an additional hour when an epidural is given).

Are the recommendations ready for prime time?
In response to the recommendations, Cohen and Friedman (author of the original labor curve) published “Perils of the new labor management guidelines,” cited above. In this commentary, they caution against universal acceptance of the guidelines without further validation. They argue that the analytical method used—and not labor itself—has changed, with possible selection biases and unadjusted confounders altering the shape of the dilatation curve. Cohen and Friedman suggest that serial evaluation of the patient is preferable to an arbitrary cutoff of 6 cm.

They also criticize other aspects of the guidelines, focusing on universal use of intrauterine pressure catheters, amniotomy, and a specific duration of pushing without consideration of descent. A “one size fits all” approach may incur risk to both the mother and the fetus without proven benefit, they contend. Clinical judgment and continuous evaluation of the likelihood and safety of vaginal delivery also are encouraged rather than a reliance on labor curves in isolation.

They urge further validation before adoption of the recommendations. “If we direct our clinical and basic science investigations to the goal of practicing obstetrics in a manner that optimizes maternal and newborn outcomes, the ideal cesarean delivery rate, whatever it may be, will follow,” they write.

What this EVIDENCE means for practice
Proceed with caution when applying labor curves to patients. Use clinical judgment in conjunction with any new guidelines.

Be vigilant for infectious threats to your obstetric population

Jamieson DJ, Uyeki TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-­gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet Gynecol. 2014;124(5):1005–1010. 

American College of Obstetricians and Gynecologists. Committee Opinion No. 614: Management of pregnant women with presumptive exposure to Listeria monocytogenes. Obstet Gynecol. 2014;124(6):1241–1244.

American College of Obstetricians and Gynecologists. Committee Opinion No. 608: Influenza vaccination during pregnancy. Obstet Gynecol. 2014;124(3):648–651.

We no longer consider pregnancy an immunosuppressed state but, rather, a more immune-modulated system. However, there is no question that the unique physiologic state of pregnancy places a woman and her fetus at increased risk for infection. This was devastatingly obvious during the H1N1 epidemic of 2009 and was reemphasized during a 2014 outbreak of Listeria monocytogenes. We are reminded again during the largest Ebola virus outbreak in history in West Africa, where women have been disproportionately affected.

No neonates have survived Ebola
Although Ebola infections in the United States have been very few, vigilance for people at risk of infection and preparedness to act in the case of infection are vitally important.

The Ebola virus is thought to be spread to humans through contact with infected fruit bats or primates. Human-to-human transmission occurs through direct contact with blood or body fluids (urine, feces, sweat, saliva, breast milk, vomit, semen) of an infected person or contaminated objects (needles, syringes). The incubation period is 2 to 21 days (average, 8–10 days).

Infected people become contagious only upon the appearance of fever and symptoms, which include headache, muscle pain, fatigue, weakness, diarrhea, abdominal pain, vomiting, bleeding, and bruising. The differential diagnosis includes malaria, typhoid, Lassa fever, meningococcal disease, influenza, and Marburg virus.

Treatment of Ebola is supportive care and isolation (standard, contact, and droplet precautions). Prevention is through infection-control precautions and isolation and testing of those exposed, with monitoring for 21 days.

Although pregnant women are not thought to be more susceptible to infection, they are at increased risk of severe illness and mortality, as well as spontaneous abortion and pregnancy-related hemorrhage. No neonates of women infected with Ebola have survived to date.

The CDC recommends that physicians screen patients who have traveled to West Africa and those with fevers and implement appropriate isolation and infection-control precautions. Many hospitals have developed Ebola task forces with this in mind.

Updated information is available at www.cdc.gov/vhf/ebola/index.html.

Pregnant women are highly susceptible to Listeriosis
A nationwide food recall in mid-2014 prompted significant media attention to ­L monocytogenes, particularly its effect on pregnant women, who have an incidence of Listerial infection 13 times higher than the general population. Although maternal illness is relatively mild, ranging from a complete lack of symptoms to febrile diarrhea, there is an increased risk to the fetus or neonate of loss, preterm labor, neonatal sepsis, meningitis, and death. The perinatal mortality rate is 29%.

The mainstay of prevention during pregnancy is improved food safety and handling, as well as counseling of pregnant women to avoid unpasteurized soft cheeses, raw milk, and unwashed fruits and vegetables, and to avoid or heat thoroughly lunch meats and hot dogs.

When a pregnant woman is exposed to Listeria, management depends on the clinical scenario, as outlined by ACOG:

Influenza is largely preventable
It is important to remember that one of the most dangerous viruses for pregnant women can be prevented. However, only 38% to 52% of women who should have received the influenza vaccine around the time of pregnancy actually did so between 2009 and 2013, according to the ACOG Committee Opinion cited above. Pregnant and postpartum women are at increased risk of serious illness, prolonged hospitalization, and death from influenza infection.

The vaccine is safe and effective. Not only does it prevent maternal morbidity and mortality, but it reduces neonatal complications. Inactivated vaccine is recommended for all pregnant women at any gestational age during the flu season.

Because many women are hesitant to accept the vaccine, accurate education is essential to dispel misconceptions about it and its components. It has been shown that if an obstetric clinician recommends the vaccine and makes it available, pregnant patients are five to 50 times more likely to receive it. As obstetricians, we are compelled to make this a priority in our practice.

What this EVIDENCE means for practice
Be alert and ready to act if an infectious threat is noted in your obstetric population. Get your flu shot. Give it to your obstetric patients. And don’t forget that ACOG also supports the administration of one dose of the tetanus, diphtheria, and pertussis vaccine during each pregnancy.

How much prenatal screening is too much?

Goetzinger KR, Odibo AO. Screening for abnormal placentation and adverse pregnancy outcomes with maternal serum biomarkers in the second trimester. Prenatal Diagn. 2014;34(7):635–641.

D’Antonio F, Rijo C, Thilaganathan B, et al. Association between first-trimester maternal serum pregnancy associated plasma protein-A and obstetric complications. Prenatal Diagn. 2013;33(9):839–847.

Dugoff L; Society for Maternal-Fetal Medicine. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol. 2010;115(5):1052–1061.

Martin A, Krishna I, Martina B, et al. Can the quantity of cell-free fetal DNA predict preeclampsia: a systematic review. Prenatal Diagn. 2014;34(7): 685–691.

Audibert F, Boucoiran I, An N, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol. 2010;203(4):383.e1–e8.

Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012;119(6):1234–1242.

The placenta of a normal pregnancy secretes small amounts of a variety of biomarkers such as alpha-fetoprotein (AFP), human chorionic gonadotropin, unconjugated estriol, inhibin A, pregnancy-associated placental protein A (PAPP-A), soluble fms-like tyrosine kinase, and placental growth factor.

The association between abnormal maternal serum biomarkers and abnormal pregnancy outcomes has been known since the 1970s, when elevated AFP was noted in pregnancies with fetal open neural tube defects. Shortly thereafter, low levels of AFP were associated with fetuses with trisomy 21.

One theory is that the abnormality in pregnancy leads to abnormal regulation at the level of the fetal-placental interface and over- or under-secretion of the various biomarkers. An offshoot of this theory is the idea that abnormal placentation (ie, preeclampsia, fetal growth restriction, accreta) also may be reflected in elevated or suppressed secretion of placental biomarkers, which could be used to screen for these conditions during pregnancy.

PAPP-A is a placental serum marker that is a component of first-trimester genetic screening. It is a marker of placental function, and low levels have been associated with fetal growth restriction, preterm birth, preeclampsia, and fetal loss. Another first-trimester marker associated with adverse outcomes is cell-free fetal DNA. This DNA, found in the maternal blood, is a product of placental apoptosis, and elevated levels have been demonstrated in women who develop preeclampsia.

Although many of the biomarkers listed here are not available specifically as a clinical screening test in the United States, the link to common genetic screens makes it tempting to try to add prediction of preeclampsia and other information to an existing test. If specific numbers are reported on the genetic screen for the different markers, that information is already there, and some companies may flag abnormally high or low levels.

However, although the association between abnormal pregnancy outcomes and abnormal biomarkers is well established in the literature, the clinical predictive value is not—nor is there always an effective intervention available. One could argue that low-dose aspirin, which is already recommended for patients with a prior delivery before 34 weeks due to preeclampsia, or more than one prior pregnancy with preeclampsia, could be recommended for patients identified on early screens to be at increased risk for preeclampsia. This approach should be tested in randomized clinical trials before universal adoption.

What this EVIDENCE means for practice
Although it is tempting to use associations to predict adverse events, the clinical value of doing so has not yet been proven. Exercise caution before potentially causing concern for both you and your patient.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Over the past year, much attention has been devoted to labor curves. Is the original Friedman labor curve, which dates to the 1950s, still applicable today? Or do contemporary women labor differently? And if we update our approach to labor management, can we reduce the rate of primary cesarean?

In this Update, we explore these questions, as well as two others:

Is adherence to new labor curves the best way to reduce the rate of primary cesarean?

American College of Obstetricians and Gynecologists. Obstetric Care Consensus No. 1: Safe prevention of the primary cesarean delivery. Obstet Gynecol. 2014;123(3):693–711.

Cohen WR, Friedman EA. Perils of the new labor management guidelines [published online ahead of print September 16, 2014]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2014.09.008.

In 2012, the cesarean delivery rate in the United States remained at 32.8%, a high percentage when one considers the increased risks that major abdominal surgery poses in both the short and long term (blood loss, transfusion, infection, venous thromboembolism, abnormal placentation, hysterectomy).¹ The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have made it a priority to reduce the cesarean delivery rate, focusing their efforts on the primary cesarean. In March 2014, they jointly issued guidelines on the “Safe prevention of the primary cesarean delivery,” highlighting labor dystocia as a top cause.

When contemporary data from the Consortium on Safe Labor were applied to the original Friedman labor curve, investigators found that the active phase of labor may be slower than previously thought.² The maximum slope for the rate of cervical change was not observed until 6 cm of dilation. This finding potentially changes the point at which arrest of the active phase may be declared. The maximum duration of augmentation with oxytocin also has been extended, based on studies that demonstrated increased vaginal delivery rates.

The Consortium on Safe Labor proposed that, by subjecting a contemporary population to decades-old standards, we have been intervening with primary cesarean too early in the treatment of labor dystocia.

What the guidelines say
The new recommendations from ACOG-SMFM suggest that arrest of the active phase of labor can be declared only when the patient is dilated at least 6 cm with ruptured membranes after either 4 hours of adequate uterine contractions or at least 6 hours of oxytocin administration with inadequate uterine contractions or no cervical change.

Although the recommendations state that there is no maximum duration of the second stage of labor, we may increase the vaginal delivery rate by increasing the duration of pushing to 2 hours for a multiparous patient and 3 hours for a nulliparous patient (with an additional hour when an epidural is given).

Are the recommendations ready for prime time?
In response to the recommendations, Cohen and Friedman (author of the original labor curve) published “Perils of the new labor management guidelines,” cited above. In this commentary, they caution against universal acceptance of the guidelines without further validation. They argue that the analytical method used—and not labor itself—has changed, with possible selection biases and unadjusted confounders altering the shape of the dilatation curve. Cohen and Friedman suggest that serial evaluation of the patient is preferable to an arbitrary cutoff of 6 cm.

They also criticize other aspects of the guidelines, focusing on universal use of intrauterine pressure catheters, amniotomy, and a specific duration of pushing without consideration of descent. A “one size fits all” approach may incur risk to both the mother and the fetus without proven benefit, they contend. Clinical judgment and continuous evaluation of the likelihood and safety of vaginal delivery also are encouraged rather than a reliance on labor curves in isolation.

They urge further validation before adoption of the recommendations. “If we direct our clinical and basic science investigations to the goal of practicing obstetrics in a manner that optimizes maternal and newborn outcomes, the ideal cesarean delivery rate, whatever it may be, will follow,” they write.

What this EVIDENCE means for practice
Proceed with caution when applying labor curves to patients. Use clinical judgment in conjunction with any new guidelines.

Be vigilant for infectious threats to your obstetric population

Jamieson DJ, Uyeki TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-­gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet Gynecol. 2014;124(5):1005–1010. 

American College of Obstetricians and Gynecologists. Committee Opinion No. 614: Management of pregnant women with presumptive exposure to Listeria monocytogenes. Obstet Gynecol. 2014;124(6):1241–1244.

American College of Obstetricians and Gynecologists. Committee Opinion No. 608: Influenza vaccination during pregnancy. Obstet Gynecol. 2014;124(3):648–651.

We no longer consider pregnancy an immunosuppressed state but, rather, a more immune-modulated system. However, there is no question that the unique physiologic state of pregnancy places a woman and her fetus at increased risk for infection. This was devastatingly obvious during the H1N1 epidemic of 2009 and was reemphasized during a 2014 outbreak of Listeria monocytogenes. We are reminded again during the largest Ebola virus outbreak in history in West Africa, where women have been disproportionately affected.

No neonates have survived Ebola
Although Ebola infections in the United States have been very few, vigilance for people at risk of infection and preparedness to act in the case of infection are vitally important.

The Ebola virus is thought to be spread to humans through contact with infected fruit bats or primates. Human-to-human transmission occurs through direct contact with blood or body fluids (urine, feces, sweat, saliva, breast milk, vomit, semen) of an infected person or contaminated objects (needles, syringes). The incubation period is 2 to 21 days (average, 8–10 days).

Infected people become contagious only upon the appearance of fever and symptoms, which include headache, muscle pain, fatigue, weakness, diarrhea, abdominal pain, vomiting, bleeding, and bruising. The differential diagnosis includes malaria, typhoid, Lassa fever, meningococcal disease, influenza, and Marburg virus.

Treatment of Ebola is supportive care and isolation (standard, contact, and droplet precautions). Prevention is through infection-control precautions and isolation and testing of those exposed, with monitoring for 21 days.

Although pregnant women are not thought to be more susceptible to infection, they are at increased risk of severe illness and mortality, as well as spontaneous abortion and pregnancy-related hemorrhage. No neonates of women infected with Ebola have survived to date.

The CDC recommends that physicians screen patients who have traveled to West Africa and those with fevers and implement appropriate isolation and infection-control precautions. Many hospitals have developed Ebola task forces with this in mind.

Updated information is available at www.cdc.gov/vhf/ebola/index.html.

Pregnant women are highly susceptible to Listeriosis
A nationwide food recall in mid-2014 prompted significant media attention to ­L monocytogenes, particularly its effect on pregnant women, who have an incidence of Listerial infection 13 times higher than the general population. Although maternal illness is relatively mild, ranging from a complete lack of symptoms to febrile diarrhea, there is an increased risk to the fetus or neonate of loss, preterm labor, neonatal sepsis, meningitis, and death. The perinatal mortality rate is 29%.

The mainstay of prevention during pregnancy is improved food safety and handling, as well as counseling of pregnant women to avoid unpasteurized soft cheeses, raw milk, and unwashed fruits and vegetables, and to avoid or heat thoroughly lunch meats and hot dogs.

When a pregnant woman is exposed to Listeria, management depends on the clinical scenario, as outlined by ACOG:

Influenza is largely preventable
It is important to remember that one of the most dangerous viruses for pregnant women can be prevented. However, only 38% to 52% of women who should have received the influenza vaccine around the time of pregnancy actually did so between 2009 and 2013, according to the ACOG Committee Opinion cited above. Pregnant and postpartum women are at increased risk of serious illness, prolonged hospitalization, and death from influenza infection.

The vaccine is safe and effective. Not only does it prevent maternal morbidity and mortality, but it reduces neonatal complications. Inactivated vaccine is recommended for all pregnant women at any gestational age during the flu season.

Because many women are hesitant to accept the vaccine, accurate education is essential to dispel misconceptions about it and its components. It has been shown that if an obstetric clinician recommends the vaccine and makes it available, pregnant patients are five to 50 times more likely to receive it. As obstetricians, we are compelled to make this a priority in our practice.

What this EVIDENCE means for practice
Be alert and ready to act if an infectious threat is noted in your obstetric population. Get your flu shot. Give it to your obstetric patients. And don’t forget that ACOG also supports the administration of one dose of the tetanus, diphtheria, and pertussis vaccine during each pregnancy.

How much prenatal screening is too much?

Goetzinger KR, Odibo AO. Screening for abnormal placentation and adverse pregnancy outcomes with maternal serum biomarkers in the second trimester. Prenatal Diagn. 2014;34(7):635–641.

D’Antonio F, Rijo C, Thilaganathan B, et al. Association between first-trimester maternal serum pregnancy associated plasma protein-A and obstetric complications. Prenatal Diagn. 2013;33(9):839–847.

Dugoff L; Society for Maternal-Fetal Medicine. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol. 2010;115(5):1052–1061.

Martin A, Krishna I, Martina B, et al. Can the quantity of cell-free fetal DNA predict preeclampsia: a systematic review. Prenatal Diagn. 2014;34(7): 685–691.

Audibert F, Boucoiran I, An N, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol. 2010;203(4):383.e1–e8.

Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012;119(6):1234–1242.

The placenta of a normal pregnancy secretes small amounts of a variety of biomarkers such as alpha-fetoprotein (AFP), human chorionic gonadotropin, unconjugated estriol, inhibin A, pregnancy-associated placental protein A (PAPP-A), soluble fms-like tyrosine kinase, and placental growth factor.

The association between abnormal maternal serum biomarkers and abnormal pregnancy outcomes has been known since the 1970s, when elevated AFP was noted in pregnancies with fetal open neural tube defects. Shortly thereafter, low levels of AFP were associated with fetuses with trisomy 21.

One theory is that the abnormality in pregnancy leads to abnormal regulation at the level of the fetal-placental interface and over- or under-secretion of the various biomarkers. An offshoot of this theory is the idea that abnormal placentation (ie, preeclampsia, fetal growth restriction, accreta) also may be reflected in elevated or suppressed secretion of placental biomarkers, which could be used to screen for these conditions during pregnancy.

PAPP-A is a placental serum marker that is a component of first-trimester genetic screening. It is a marker of placental function, and low levels have been associated with fetal growth restriction, preterm birth, preeclampsia, and fetal loss. Another first-trimester marker associated with adverse outcomes is cell-free fetal DNA. This DNA, found in the maternal blood, is a product of placental apoptosis, and elevated levels have been demonstrated in women who develop preeclampsia.

Although many of the biomarkers listed here are not available specifically as a clinical screening test in the United States, the link to common genetic screens makes it tempting to try to add prediction of preeclampsia and other information to an existing test. If specific numbers are reported on the genetic screen for the different markers, that information is already there, and some companies may flag abnormally high or low levels.

However, although the association between abnormal pregnancy outcomes and abnormal biomarkers is well established in the literature, the clinical predictive value is not—nor is there always an effective intervention available. One could argue that low-dose aspirin, which is already recommended for patients with a prior delivery before 34 weeks due to preeclampsia, or more than one prior pregnancy with preeclampsia, could be recommended for patients identified on early screens to be at increased risk for preeclampsia. This approach should be tested in randomized clinical trials before universal adoption.

What this EVIDENCE means for practice
Although it is tempting to use associations to predict adverse events, the clinical value of doing so has not yet been proven. Exercise caution before potentially causing concern for both you and your patient.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Over the past year, much attention has been devoted to labor curves. Is the original Friedman labor curve, which dates to the 1950s, still applicable today? Or do contemporary women labor differently? And if we update our approach to labor management, can we reduce the rate of primary cesarean?

In this Update, we explore these questions, as well as two others:

Is adherence to new labor curves the best way to reduce the rate of primary cesarean?

American College of Obstetricians and Gynecologists. Obstetric Care Consensus No. 1: Safe prevention of the primary cesarean delivery. Obstet Gynecol. 2014;123(3):693–711.

Cohen WR, Friedman EA. Perils of the new labor management guidelines [published online ahead of print September 16, 2014]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2014.09.008.

In 2012, the cesarean delivery rate in the United States remained at 32.8%, a high percentage when one considers the increased risks that major abdominal surgery poses in both the short and long term (blood loss, transfusion, infection, venous thromboembolism, abnormal placentation, hysterectomy).¹ The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have made it a priority to reduce the cesarean delivery rate, focusing their efforts on the primary cesarean. In March 2014, they jointly issued guidelines on the “Safe prevention of the primary cesarean delivery,” highlighting labor dystocia as a top cause.

When contemporary data from the Consortium on Safe Labor were applied to the original Friedman labor curve, investigators found that the active phase of labor may be slower than previously thought.² The maximum slope for the rate of cervical change was not observed until 6 cm of dilation. This finding potentially changes the point at which arrest of the active phase may be declared. The maximum duration of augmentation with oxytocin also has been extended, based on studies that demonstrated increased vaginal delivery rates.

The Consortium on Safe Labor proposed that, by subjecting a contemporary population to decades-old standards, we have been intervening with primary cesarean too early in the treatment of labor dystocia.

What the guidelines say
The new recommendations from ACOG-SMFM suggest that arrest of the active phase of labor can be declared only when the patient is dilated at least 6 cm with ruptured membranes after either 4 hours of adequate uterine contractions or at least 6 hours of oxytocin administration with inadequate uterine contractions or no cervical change.

Although the recommendations state that there is no maximum duration of the second stage of labor, we may increase the vaginal delivery rate by increasing the duration of pushing to 2 hours for a multiparous patient and 3 hours for a nulliparous patient (with an additional hour when an epidural is given).

Are the recommendations ready for prime time?
In response to the recommendations, Cohen and Friedman (author of the original labor curve) published “Perils of the new labor management guidelines,” cited above. In this commentary, they caution against universal acceptance of the guidelines without further validation. They argue that the analytical method used—and not labor itself—has changed, with possible selection biases and unadjusted confounders altering the shape of the dilatation curve. Cohen and Friedman suggest that serial evaluation of the patient is preferable to an arbitrary cutoff of 6 cm.

They also criticize other aspects of the guidelines, focusing on universal use of intrauterine pressure catheters, amniotomy, and a specific duration of pushing without consideration of descent. A “one size fits all” approach may incur risk to both the mother and the fetus without proven benefit, they contend. Clinical judgment and continuous evaluation of the likelihood and safety of vaginal delivery also are encouraged rather than a reliance on labor curves in isolation.

They urge further validation before adoption of the recommendations. “If we direct our clinical and basic science investigations to the goal of practicing obstetrics in a manner that optimizes maternal and newborn outcomes, the ideal cesarean delivery rate, whatever it may be, will follow,” they write.

What this EVIDENCE means for practice
Proceed with caution when applying labor curves to patients. Use clinical judgment in conjunction with any new guidelines.

Be vigilant for infectious threats to your obstetric population

Jamieson DJ, Uyeki TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-­gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet Gynecol. 2014;124(5):1005–1010. 

American College of Obstetricians and Gynecologists. Committee Opinion No. 614: Management of pregnant women with presumptive exposure to Listeria monocytogenes. Obstet Gynecol. 2014;124(6):1241–1244.

American College of Obstetricians and Gynecologists. Committee Opinion No. 608: Influenza vaccination during pregnancy. Obstet Gynecol. 2014;124(3):648–651.

We no longer consider pregnancy an immunosuppressed state but, rather, a more immune-modulated system. However, there is no question that the unique physiologic state of pregnancy places a woman and her fetus at increased risk for infection. This was devastatingly obvious during the H1N1 epidemic of 2009 and was reemphasized during a 2014 outbreak of Listeria monocytogenes. We are reminded again during the largest Ebola virus outbreak in history in West Africa, where women have been disproportionately affected.

No neonates have survived Ebola
Although Ebola infections in the United States have been very few, vigilance for people at risk of infection and preparedness to act in the case of infection are vitally important.

The Ebola virus is thought to be spread to humans through contact with infected fruit bats or primates. Human-to-human transmission occurs through direct contact with blood or body fluids (urine, feces, sweat, saliva, breast milk, vomit, semen) of an infected person or contaminated objects (needles, syringes). The incubation period is 2 to 21 days (average, 8–10 days).

Infected people become contagious only upon the appearance of fever and symptoms, which include headache, muscle pain, fatigue, weakness, diarrhea, abdominal pain, vomiting, bleeding, and bruising. The differential diagnosis includes malaria, typhoid, Lassa fever, meningococcal disease, influenza, and Marburg virus.

Treatment of Ebola is supportive care and isolation (standard, contact, and droplet precautions). Prevention is through infection-control precautions and isolation and testing of those exposed, with monitoring for 21 days.

Although pregnant women are not thought to be more susceptible to infection, they are at increased risk of severe illness and mortality, as well as spontaneous abortion and pregnancy-related hemorrhage. No neonates of women infected with Ebola have survived to date.

The CDC recommends that physicians screen patients who have traveled to West Africa and those with fevers and implement appropriate isolation and infection-control precautions. Many hospitals have developed Ebola task forces with this in mind.

Updated information is available at www.cdc.gov/vhf/ebola/index.html.

Pregnant women are highly susceptible to Listeriosis
A nationwide food recall in mid-2014 prompted significant media attention to ­L monocytogenes, particularly its effect on pregnant women, who have an incidence of Listerial infection 13 times higher than the general population. Although maternal illness is relatively mild, ranging from a complete lack of symptoms to febrile diarrhea, there is an increased risk to the fetus or neonate of loss, preterm labor, neonatal sepsis, meningitis, and death. The perinatal mortality rate is 29%.

The mainstay of prevention during pregnancy is improved food safety and handling, as well as counseling of pregnant women to avoid unpasteurized soft cheeses, raw milk, and unwashed fruits and vegetables, and to avoid or heat thoroughly lunch meats and hot dogs.

When a pregnant woman is exposed to Listeria, management depends on the clinical scenario, as outlined by ACOG:

Influenza is largely preventable
It is important to remember that one of the most dangerous viruses for pregnant women can be prevented. However, only 38% to 52% of women who should have received the influenza vaccine around the time of pregnancy actually did so between 2009 and 2013, according to the ACOG Committee Opinion cited above. Pregnant and postpartum women are at increased risk of serious illness, prolonged hospitalization, and death from influenza infection.

The vaccine is safe and effective. Not only does it prevent maternal morbidity and mortality, but it reduces neonatal complications. Inactivated vaccine is recommended for all pregnant women at any gestational age during the flu season.

Because many women are hesitant to accept the vaccine, accurate education is essential to dispel misconceptions about it and its components. It has been shown that if an obstetric clinician recommends the vaccine and makes it available, pregnant patients are five to 50 times more likely to receive it. As obstetricians, we are compelled to make this a priority in our practice.

What this EVIDENCE means for practice
Be alert and ready to act if an infectious threat is noted in your obstetric population. Get your flu shot. Give it to your obstetric patients. And don’t forget that ACOG also supports the administration of one dose of the tetanus, diphtheria, and pertussis vaccine during each pregnancy.

How much prenatal screening is too much?

Goetzinger KR, Odibo AO. Screening for abnormal placentation and adverse pregnancy outcomes with maternal serum biomarkers in the second trimester. Prenatal Diagn. 2014;34(7):635–641.

D’Antonio F, Rijo C, Thilaganathan B, et al. Association between first-trimester maternal serum pregnancy associated plasma protein-A and obstetric complications. Prenatal Diagn. 2013;33(9):839–847.

Dugoff L; Society for Maternal-Fetal Medicine. First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes. Obstet Gynecol. 2010;115(5):1052–1061.

Martin A, Krishna I, Martina B, et al. Can the quantity of cell-free fetal DNA predict preeclampsia: a systematic review. Prenatal Diagn. 2014;34(7): 685–691.

Audibert F, Boucoiran I, An N, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol. 2010;203(4):383.e1–e8.

Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012;119(6):1234–1242.

The placenta of a normal pregnancy secretes small amounts of a variety of biomarkers such as alpha-fetoprotein (AFP), human chorionic gonadotropin, unconjugated estriol, inhibin A, pregnancy-associated placental protein A (PAPP-A), soluble fms-like tyrosine kinase, and placental growth factor.

The association between abnormal maternal serum biomarkers and abnormal pregnancy outcomes has been known since the 1970s, when elevated AFP was noted in pregnancies with fetal open neural tube defects. Shortly thereafter, low levels of AFP were associated with fetuses with trisomy 21.

One theory is that the abnormality in pregnancy leads to abnormal regulation at the level of the fetal-placental interface and over- or under-secretion of the various biomarkers. An offshoot of this theory is the idea that abnormal placentation (ie, preeclampsia, fetal growth restriction, accreta) also may be reflected in elevated or suppressed secretion of placental biomarkers, which could be used to screen for these conditions during pregnancy.

PAPP-A is a placental serum marker that is a component of first-trimester genetic screening. It is a marker of placental function, and low levels have been associated with fetal growth restriction, preterm birth, preeclampsia, and fetal loss. Another first-trimester marker associated with adverse outcomes is cell-free fetal DNA. This DNA, found in the maternal blood, is a product of placental apoptosis, and elevated levels have been demonstrated in women who develop preeclampsia.

Although many of the biomarkers listed here are not available specifically as a clinical screening test in the United States, the link to common genetic screens makes it tempting to try to add prediction of preeclampsia and other information to an existing test. If specific numbers are reported on the genetic screen for the different markers, that information is already there, and some companies may flag abnormally high or low levels.

However, although the association between abnormal pregnancy outcomes and abnormal biomarkers is well established in the literature, the clinical predictive value is not—nor is there always an effective intervention available. One could argue that low-dose aspirin, which is already recommended for patients with a prior delivery before 34 weeks due to preeclampsia, or more than one prior pregnancy with preeclampsia, could be recommended for patients identified on early screens to be at increased risk for preeclampsia. This approach should be tested in randomized clinical trials before universal adoption.

What this EVIDENCE means for practice
Although it is tempting to use associations to predict adverse events, the clinical value of doing so has not yet been proven. Exercise caution before potentially causing concern for both you and your patient.

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