Our specialty is focusing now more intently on perioperative optimization, commonly referred to as enhanced recovery after surgery (ERAS), a concept championed first and most visibly by colorectal surgeons in the 1990s.¹ Both academic and nonacademic practices are challenging long-held beliefs about perioperative management.

The 3 tenets of ERAS

In multiple surgical specialties, proper implementation of 3 tenets—early feeding, perioperative euvolemia, and multimodal pain control—reduces the length of hospital stay, improves patient satisfaction, reduces complications, lowers health care costs, and most importantly hastens patient recovery.

1 Early feeding

Just as athletes hydrate and carbohydrate load prior to a competition, patients benefit if fluids and calories are not withheld in anticipation of a physiologically stressful surgical procedure. Similarly, modest benefit is associated with carbohydrate loading as a liquid supplement 2 hours before surgery.² The American Society of Anesthesiologists guidelines state that while solid foods should not be consumed after midnight before surgery, clear liquids safely may be withheld for only 2 hours prior to anesthesia induction, and systematic reviews have failed to show harm.^3,4 All patients, including those undergoing colonic resections, are allowed to eat a general diet as tolerated the evening before surgery, supplemented with caloric-dense nutritional supplements.

2 Multimodal pain control

Postsurgical pain is a top patient concern. Pain control is critical for rapid recovery; it helps avoid upregulation of the sympathetic axis and permits ambulation and resumption of normal activities. Although opioids relieve pain, they should not be considered a primary pain control approach.

Responding to the opioid epidemic, in 2015 the Centers for Disease Control and Prevention identified opioid overdose prevention as one of the top 5 public health challenges; notably, approximately 6% of patients will experience new, persistent opioid use following surgery.⁵ Optimal pain management therefore should provide effective pain relief while minimizing opioid use.

Preemptive oral acetaminophen, gabapentin, and celecoxib should be used routinely prior to incision; nonsteroidal anti-inflammatory drugs should be scheduled postoperatively. Even after a complex cytoreductive laparotomy, pain may be controlled with oral rather than intravenous (IV) medications in most patients, with opioid requirements averaging just 2 to 4 tablets of oxycodone in the first 48 hours after surgery, in our experience. The most critical need for pain medications occurs in the first 48 hours after surgery, which highlights the importance of local or regional analgesia. In one investigation, implementation of multimodal pain management that included incisional injection of liposomal bupivacaine reduced patient-controlled analgesia use to less than 5% after laparotomy.⁶ The need for opioids more than a week postoperatively is uncommon even after a laparotomy.

3 Perioperative euvolemia

Maintaining euvolemia is a central and underrecognized tenet of enhanced recovery pathways, and it facilitates the other 2 tenets of early feeding and optimal pain control. Overhydrated patients have more pain and prolonged recovery of bowel function. Unfortunately, euvolemia is the most difficult ERAS component to implement, requiring seamless communication between all members of the surgical team.

Continue to: Fluid therapy...

Fluid therapy should be respected as a pharmacologic agent with both benefits and risks. Recognizing that a single liter of lactated Ringer’s solution contains the sodium load of more than 30 bags of potato chips (and normal saline contains far more), one can imagine the impact of 10 L of solution on peripheral and bowel edema and on overall recovery. Importantly, euvolemia must be initiated during surgery. A meta-analysis of nearly 1,000 randomly assigned patients showed that benefits were limited when euvolemia was initiated in the postoperative period.⁷

When it comes to maintaining euvolemia, particular care must be taken to avoid erring toward hyperadherence. No difference in hospital length of stay, complications, or ileus was observed when patients were randomly assigned to goal-directed fluid therapy or standard practice.⁸ However, differences in the volume of fluid administered were relatively small, and while there was evidence of underhydration (likely responsible for acute kidney injury), there was no evidence of overhydration. For example, 4 L of fluid is likely superior to 15 L, but it may not be clinically different from 4.5 L. A threshold of fluid restriction is likely to be reached; that is, additional benefit is not achieved and, instead, detrimental effects may occur.

Rather than a specific directive, a more clinically relevant goal may be to replace insensible fluid losses and to maintain perfusion and blood pressure with the lowest volume possible. Note that estimation of fluid requirements is vastly simplified by omitting mechanical bowel preparation. Postoperatively, permissive oliguria (20 mL/h) is allowed since reduced urine output is a normal response to surgery (as a result of inappropriate secretion of antidiuretic hormone) and does not necessitate administration of a fluid bolus. Above all, anesthesiologists should acknowledge that fluid administration’s effects on a patient extend past the postanesthesia care unit, and the entire surgical team should be invested in the patient’s long-term recovery.

Our experience with ERAS

In 2011, Mayo Clinic was the first institution to implement enhanced recovery on a large scale in gynecologic surgery. We have subsequently made multiple pathway modifications in the spirit of continuous improvement (FIGURE 1).

For patients with ovarian cancer requiring extended procedures for cytoreduction via laparotomy (such as colon resection, splenectomy, diaphragm resection), enhanced recovery reduced the median hospital stay by 3 days, patient-controlled IV analgesia use by 88%, and postoperative opioid requirements by 90%.^9,10

At 48 hours after surgery, 40% of our patients require no opioids or tramadol, and epidurals are not utilized because of their effects on ambulation and the potential for hypotension. These reductions were met with stable to improved pain scores, a 60% decrease in nausea, and a 50% reduction in adynamic ileus.^9,10

Our initial efforts reduced 30-day costs of care by more than $850,000 in just 6 months, with savings of more than $7,600 for each patient undergoing a complex cytoreduction. Furthermore, these improvements allowed consolidation of our inpatient unit with those of other surgical specialties, serving higher volumes of patients within a smaller inpatient footprint. This contraction of inpatient services has accounted for an additional $1.1 million in savings every year since implementation (FIGURE 2).^9,10

Our group is not alone in realizing these benefits, and interest has intensified as demonstrated by the fact that the ERAS Society guidelines are among the all-time most downloaded articles in Gynecologic Oncology.^11,12 Although our research to demonstrate safety has focused on women undergoing complex oncologic operations, ERAS nevertheless hastens recovery, improves patient satisfaction, and adds value for all patients undergoing gynecologic surgery.

Continue to: Collateral improvements to practice...

Collateral improvements to practice

Clinical optimization using evidence-based practices such as enhanced recovery pathways can result in immediate patient benefit. Affecting such profound clinical improvements is energizing and creates a unique opportunity to transform the culture of the entire health care team. Irrespective of our provider roles (surgeon, anesthesiologist, nurse) or areas of interest (practice, research, education, leadership), we are united by a common purpose: to improve the human condition.¹³ Reaffirming this common purpose, through the collective effort involved in establishing a standardized enhanced recovery pathway, has allowed our practice and those of others to move beyond enhanced recovery and improve other areas of practice.

Other positive effects. The long-term collateral impact of this culture change at our institution is arguably more important than enhanced recovery itself. Examples of downstream impact include^14,15:

• 80% reduction in surgical site infection
• 50% reduction in anastomotic leaks
• 60% reduction in blood utilization for patients undergoing surgery for ovarian cancer.

Team-based pragmatic strategies. Additionally, our willingness to make decisions as a division rather than as individuals facilitated universal implementation of sentinel lymph node biopsy for patients with endometrial cancer and standardized imaging, testing, and surgical decision making for patients with ovarian and endometrial cancer.

The interventions associated with these improvements were not tested in a randomized fashion; however, rather than await perfect data, we made informed decisions based on imperfect data together with a commitment to continuous data review. We find this to be an effective strategy if our goal is to ensure that tomorrow’s outcomes will be better than yesterday’s. In this way, pragmatic trials can be extremely effective in rural settings and tertiary centers.

Barriers to innovation

The widely reported benefits of enhanced recovery beg the question, Why has enhanced recovery not been adopted universally as standard of care? The answer is multifaceted and highlights long-standing shortcomings in our health care system.

Most importantly, our health care system lacks a robust interface to link discovery of new techniques, treatments, and workflows to clinical practice. Perhaps the best example of this is the adoption of minimally invasive surgery (MIS) for endometrial cancer. Ten years have passed since randomized trials showed MIS has equivalent oncologic outcomes and superior recovery compared to laparotomy, yet in the United States less than 50% of women with endometrial cancer benefit.^16,17

However, even surgeons who are knowledgeable about recent innovations and genuinely wish to promote improvements may face near-insurmountable skepticism. Blind faith in our abilities and outcomes, overprotection of autonomy, close-mindedness, and satisfaction with the status quo are common responses to innovation and are the enemies of change. Resistance often comes from good intentions, but our desire to avoid complications may result in actions that could just as accurately be labeled superstitious as conservative. These observations suggest that developing methods to incorporate evidence-based practice into routine clinical use is the rate-limiting step in improving surgical quality.

Principles essential to change

Various methodologies have been described to manage change and facilitate implementation of new workflows and practices. Irrespective of the method used, including the more formal discipline of implementation science, at least 4 principles must be followed:

1. Teamwork. Mutual trust, mutual respect, and a sense of common purpose are minimum requirements for any successful initiative. Standardization is difficult or impossible without these elements. Thus, establishing a healthy team is the first step in implementing change.

2. Stakeholder analysis. Feedback from surgeons, nurses, residents, fellows, anesthesiologists, pharmacists, nurse anesthetists, and administrators is necessary to obtain diverse perspectives, facilitate engagement, and promote collaborative management. Negativity and resistance are common reactions to change, and it is particularly important to include those who are most skeptical in the stakeholder analysis to mitigate sabotage.

3. Concrete metrics. Success is possible only if defined a priori by specific and achievable goals. Counterbalances also are important to ensure that interventions do not have unintended consequences. Once a goal is met (for example, reduced hospital length of stay or costs), relevant metrics should be monitored after project completion for a minimum of 3 years to avoid regression to the pre-project state.

4. Leadership. The project champion responsible for the initiative must objectively facilitate all of the above and ensure excellent communication between stakeholders to nurture long-term engagement. Despite best efforts, if a minority of the group rejects compromise, this creates an opportunity to compare outcomes between those who do and do not accept the proposed change. Progress realized by early adopters may convince resistors to conform at a later time. Alternatively, the project champion also must have the insight to recognize when a proposed change is impossible at that point in time with that particular group. For example, our own initial attempts to implement enhanced recovery stalled in 2008, but they were successful 3 years later in a different environment.

Continue to: Although a discussion of leadership styles...

Although a discussion of leadership styles is beyond the scope of this article, in our experience, the most successful model is one of servant leadership that is team oriented rather than star dominated. Rather than being led by a single surgeon, each of the 4 quality improvement projects reviewed above (ERAS, and reductions in anastomotic leak, surgical site infection, and blood transfusion) that grew from enhanced recovery included trainees and was led by a different champion, encouraging teamwork and promoting career development. Such a model also supports the Accreditation Council for Graduate Medical Education’s emphasis on quality improvement education.

Our specialty is focusing now more intently on perioperative optimization, commonly referred to as enhanced recovery after surgery (ERAS), a concept championed first and most visibly by colorectal surgeons in the 1990s.¹ Both academic and nonacademic practices are challenging long-held beliefs about perioperative management.

The 3 tenets of ERAS

In multiple surgical specialties, proper implementation of 3 tenets—early feeding, perioperative euvolemia, and multimodal pain control—reduces the length of hospital stay, improves patient satisfaction, reduces complications, lowers health care costs, and most importantly hastens patient recovery.

1 Early feeding

Just as athletes hydrate and carbohydrate load prior to a competition, patients benefit if fluids and calories are not withheld in anticipation of a physiologically stressful surgical procedure. Similarly, modest benefit is associated with carbohydrate loading as a liquid supplement 2 hours before surgery.² The American Society of Anesthesiologists guidelines state that while solid foods should not be consumed after midnight before surgery, clear liquids safely may be withheld for only 2 hours prior to anesthesia induction, and systematic reviews have failed to show harm.^3,4 All patients, including those undergoing colonic resections, are allowed to eat a general diet as tolerated the evening before surgery, supplemented with caloric-dense nutritional supplements.

2 Multimodal pain control

Postsurgical pain is a top patient concern. Pain control is critical for rapid recovery; it helps avoid upregulation of the sympathetic axis and permits ambulation and resumption of normal activities. Although opioids relieve pain, they should not be considered a primary pain control approach.

Responding to the opioid epidemic, in 2015 the Centers for Disease Control and Prevention identified opioid overdose prevention as one of the top 5 public health challenges; notably, approximately 6% of patients will experience new, persistent opioid use following surgery.⁵ Optimal pain management therefore should provide effective pain relief while minimizing opioid use.

Preemptive oral acetaminophen, gabapentin, and celecoxib should be used routinely prior to incision; nonsteroidal anti-inflammatory drugs should be scheduled postoperatively. Even after a complex cytoreductive laparotomy, pain may be controlled with oral rather than intravenous (IV) medications in most patients, with opioid requirements averaging just 2 to 4 tablets of oxycodone in the first 48 hours after surgery, in our experience. The most critical need for pain medications occurs in the first 48 hours after surgery, which highlights the importance of local or regional analgesia. In one investigation, implementation of multimodal pain management that included incisional injection of liposomal bupivacaine reduced patient-controlled analgesia use to less than 5% after laparotomy.⁶ The need for opioids more than a week postoperatively is uncommon even after a laparotomy.

3 Perioperative euvolemia

Maintaining euvolemia is a central and underrecognized tenet of enhanced recovery pathways, and it facilitates the other 2 tenets of early feeding and optimal pain control. Overhydrated patients have more pain and prolonged recovery of bowel function. Unfortunately, euvolemia is the most difficult ERAS component to implement, requiring seamless communication between all members of the surgical team.

Continue to: Fluid therapy...

Fluid therapy should be respected as a pharmacologic agent with both benefits and risks. Recognizing that a single liter of lactated Ringer’s solution contains the sodium load of more than 30 bags of potato chips (and normal saline contains far more), one can imagine the impact of 10 L of solution on peripheral and bowel edema and on overall recovery. Importantly, euvolemia must be initiated during surgery. A meta-analysis of nearly 1,000 randomly assigned patients showed that benefits were limited when euvolemia was initiated in the postoperative period.⁷

When it comes to maintaining euvolemia, particular care must be taken to avoid erring toward hyperadherence. No difference in hospital length of stay, complications, or ileus was observed when patients were randomly assigned to goal-directed fluid therapy or standard practice.⁸ However, differences in the volume of fluid administered were relatively small, and while there was evidence of underhydration (likely responsible for acute kidney injury), there was no evidence of overhydration. For example, 4 L of fluid is likely superior to 15 L, but it may not be clinically different from 4.5 L. A threshold of fluid restriction is likely to be reached; that is, additional benefit is not achieved and, instead, detrimental effects may occur.

Rather than a specific directive, a more clinically relevant goal may be to replace insensible fluid losses and to maintain perfusion and blood pressure with the lowest volume possible. Note that estimation of fluid requirements is vastly simplified by omitting mechanical bowel preparation. Postoperatively, permissive oliguria (20 mL/h) is allowed since reduced urine output is a normal response to surgery (as a result of inappropriate secretion of antidiuretic hormone) and does not necessitate administration of a fluid bolus. Above all, anesthesiologists should acknowledge that fluid administration’s effects on a patient extend past the postanesthesia care unit, and the entire surgical team should be invested in the patient’s long-term recovery.

Our experience with ERAS

In 2011, Mayo Clinic was the first institution to implement enhanced recovery on a large scale in gynecologic surgery. We have subsequently made multiple pathway modifications in the spirit of continuous improvement (FIGURE 1).

For patients with ovarian cancer requiring extended procedures for cytoreduction via laparotomy (such as colon resection, splenectomy, diaphragm resection), enhanced recovery reduced the median hospital stay by 3 days, patient-controlled IV analgesia use by 88%, and postoperative opioid requirements by 90%.^9,10

At 48 hours after surgery, 40% of our patients require no opioids or tramadol, and epidurals are not utilized because of their effects on ambulation and the potential for hypotension. These reductions were met with stable to improved pain scores, a 60% decrease in nausea, and a 50% reduction in adynamic ileus.^9,10

Our initial efforts reduced 30-day costs of care by more than $850,000 in just 6 months, with savings of more than $7,600 for each patient undergoing a complex cytoreduction. Furthermore, these improvements allowed consolidation of our inpatient unit with those of other surgical specialties, serving higher volumes of patients within a smaller inpatient footprint. This contraction of inpatient services has accounted for an additional $1.1 million in savings every year since implementation (FIGURE 2).^9,10

Our group is not alone in realizing these benefits, and interest has intensified as demonstrated by the fact that the ERAS Society guidelines are among the all-time most downloaded articles in Gynecologic Oncology.^11,12 Although our research to demonstrate safety has focused on women undergoing complex oncologic operations, ERAS nevertheless hastens recovery, improves patient satisfaction, and adds value for all patients undergoing gynecologic surgery.

Continue to: Collateral improvements to practice...

Collateral improvements to practice

Clinical optimization using evidence-based practices such as enhanced recovery pathways can result in immediate patient benefit. Affecting such profound clinical improvements is energizing and creates a unique opportunity to transform the culture of the entire health care team. Irrespective of our provider roles (surgeon, anesthesiologist, nurse) or areas of interest (practice, research, education, leadership), we are united by a common purpose: to improve the human condition.¹³ Reaffirming this common purpose, through the collective effort involved in establishing a standardized enhanced recovery pathway, has allowed our practice and those of others to move beyond enhanced recovery and improve other areas of practice.

Other positive effects. The long-term collateral impact of this culture change at our institution is arguably more important than enhanced recovery itself. Examples of downstream impact include^14,15:

• 80% reduction in surgical site infection
• 50% reduction in anastomotic leaks
• 60% reduction in blood utilization for patients undergoing surgery for ovarian cancer.

Team-based pragmatic strategies. Additionally, our willingness to make decisions as a division rather than as individuals facilitated universal implementation of sentinel lymph node biopsy for patients with endometrial cancer and standardized imaging, testing, and surgical decision making for patients with ovarian and endometrial cancer.

The interventions associated with these improvements were not tested in a randomized fashion; however, rather than await perfect data, we made informed decisions based on imperfect data together with a commitment to continuous data review. We find this to be an effective strategy if our goal is to ensure that tomorrow’s outcomes will be better than yesterday’s. In this way, pragmatic trials can be extremely effective in rural settings and tertiary centers.

Barriers to innovation

The widely reported benefits of enhanced recovery beg the question, Why has enhanced recovery not been adopted universally as standard of care? The answer is multifaceted and highlights long-standing shortcomings in our health care system.

Most importantly, our health care system lacks a robust interface to link discovery of new techniques, treatments, and workflows to clinical practice. Perhaps the best example of this is the adoption of minimally invasive surgery (MIS) for endometrial cancer. Ten years have passed since randomized trials showed MIS has equivalent oncologic outcomes and superior recovery compared to laparotomy, yet in the United States less than 50% of women with endometrial cancer benefit.^16,17

However, even surgeons who are knowledgeable about recent innovations and genuinely wish to promote improvements may face near-insurmountable skepticism. Blind faith in our abilities and outcomes, overprotection of autonomy, close-mindedness, and satisfaction with the status quo are common responses to innovation and are the enemies of change. Resistance often comes from good intentions, but our desire to avoid complications may result in actions that could just as accurately be labeled superstitious as conservative. These observations suggest that developing methods to incorporate evidence-based practice into routine clinical use is the rate-limiting step in improving surgical quality.

Principles essential to change

Various methodologies have been described to manage change and facilitate implementation of new workflows and practices. Irrespective of the method used, including the more formal discipline of implementation science, at least 4 principles must be followed:

1. Teamwork. Mutual trust, mutual respect, and a sense of common purpose are minimum requirements for any successful initiative. Standardization is difficult or impossible without these elements. Thus, establishing a healthy team is the first step in implementing change.

2. Stakeholder analysis. Feedback from surgeons, nurses, residents, fellows, anesthesiologists, pharmacists, nurse anesthetists, and administrators is necessary to obtain diverse perspectives, facilitate engagement, and promote collaborative management. Negativity and resistance are common reactions to change, and it is particularly important to include those who are most skeptical in the stakeholder analysis to mitigate sabotage.

3. Concrete metrics. Success is possible only if defined a priori by specific and achievable goals. Counterbalances also are important to ensure that interventions do not have unintended consequences. Once a goal is met (for example, reduced hospital length of stay or costs), relevant metrics should be monitored after project completion for a minimum of 3 years to avoid regression to the pre-project state.

4. Leadership. The project champion responsible for the initiative must objectively facilitate all of the above and ensure excellent communication between stakeholders to nurture long-term engagement. Despite best efforts, if a minority of the group rejects compromise, this creates an opportunity to compare outcomes between those who do and do not accept the proposed change. Progress realized by early adopters may convince resistors to conform at a later time. Alternatively, the project champion also must have the insight to recognize when a proposed change is impossible at that point in time with that particular group. For example, our own initial attempts to implement enhanced recovery stalled in 2008, but they were successful 3 years later in a different environment.

Continue to: Although a discussion of leadership styles...

Although a discussion of leadership styles is beyond the scope of this article, in our experience, the most successful model is one of servant leadership that is team oriented rather than star dominated. Rather than being led by a single surgeon, each of the 4 quality improvement projects reviewed above (ERAS, and reductions in anastomotic leak, surgical site infection, and blood transfusion) that grew from enhanced recovery included trainees and was led by a different champion, encouraging teamwork and promoting career development. Such a model also supports the Accreditation Council for Graduate Medical Education’s emphasis on quality improvement education.

Our specialty is focusing now more intently on perioperative optimization, commonly referred to as enhanced recovery after surgery (ERAS), a concept championed first and most visibly by colorectal surgeons in the 1990s.¹ Both academic and nonacademic practices are challenging long-held beliefs about perioperative management.

The 3 tenets of ERAS

In multiple surgical specialties, proper implementation of 3 tenets—early feeding, perioperative euvolemia, and multimodal pain control—reduces the length of hospital stay, improves patient satisfaction, reduces complications, lowers health care costs, and most importantly hastens patient recovery.

1 Early feeding

Just as athletes hydrate and carbohydrate load prior to a competition, patients benefit if fluids and calories are not withheld in anticipation of a physiologically stressful surgical procedure. Similarly, modest benefit is associated with carbohydrate loading as a liquid supplement 2 hours before surgery.² The American Society of Anesthesiologists guidelines state that while solid foods should not be consumed after midnight before surgery, clear liquids safely may be withheld for only 2 hours prior to anesthesia induction, and systematic reviews have failed to show harm.^3,4 All patients, including those undergoing colonic resections, are allowed to eat a general diet as tolerated the evening before surgery, supplemented with caloric-dense nutritional supplements.

2 Multimodal pain control

Postsurgical pain is a top patient concern. Pain control is critical for rapid recovery; it helps avoid upregulation of the sympathetic axis and permits ambulation and resumption of normal activities. Although opioids relieve pain, they should not be considered a primary pain control approach.

Responding to the opioid epidemic, in 2015 the Centers for Disease Control and Prevention identified opioid overdose prevention as one of the top 5 public health challenges; notably, approximately 6% of patients will experience new, persistent opioid use following surgery.⁵ Optimal pain management therefore should provide effective pain relief while minimizing opioid use.

Preemptive oral acetaminophen, gabapentin, and celecoxib should be used routinely prior to incision; nonsteroidal anti-inflammatory drugs should be scheduled postoperatively. Even after a complex cytoreductive laparotomy, pain may be controlled with oral rather than intravenous (IV) medications in most patients, with opioid requirements averaging just 2 to 4 tablets of oxycodone in the first 48 hours after surgery, in our experience. The most critical need for pain medications occurs in the first 48 hours after surgery, which highlights the importance of local or regional analgesia. In one investigation, implementation of multimodal pain management that included incisional injection of liposomal bupivacaine reduced patient-controlled analgesia use to less than 5% after laparotomy.⁶ The need for opioids more than a week postoperatively is uncommon even after a laparotomy.

3 Perioperative euvolemia

Maintaining euvolemia is a central and underrecognized tenet of enhanced recovery pathways, and it facilitates the other 2 tenets of early feeding and optimal pain control. Overhydrated patients have more pain and prolonged recovery of bowel function. Unfortunately, euvolemia is the most difficult ERAS component to implement, requiring seamless communication between all members of the surgical team.

Continue to: Fluid therapy...

Fluid therapy should be respected as a pharmacologic agent with both benefits and risks. Recognizing that a single liter of lactated Ringer’s solution contains the sodium load of more than 30 bags of potato chips (and normal saline contains far more), one can imagine the impact of 10 L of solution on peripheral and bowel edema and on overall recovery. Importantly, euvolemia must be initiated during surgery. A meta-analysis of nearly 1,000 randomly assigned patients showed that benefits were limited when euvolemia was initiated in the postoperative period.⁷

When it comes to maintaining euvolemia, particular care must be taken to avoid erring toward hyperadherence. No difference in hospital length of stay, complications, or ileus was observed when patients were randomly assigned to goal-directed fluid therapy or standard practice.⁸ However, differences in the volume of fluid administered were relatively small, and while there was evidence of underhydration (likely responsible for acute kidney injury), there was no evidence of overhydration. For example, 4 L of fluid is likely superior to 15 L, but it may not be clinically different from 4.5 L. A threshold of fluid restriction is likely to be reached; that is, additional benefit is not achieved and, instead, detrimental effects may occur.

Rather than a specific directive, a more clinically relevant goal may be to replace insensible fluid losses and to maintain perfusion and blood pressure with the lowest volume possible. Note that estimation of fluid requirements is vastly simplified by omitting mechanical bowel preparation. Postoperatively, permissive oliguria (20 mL/h) is allowed since reduced urine output is a normal response to surgery (as a result of inappropriate secretion of antidiuretic hormone) and does not necessitate administration of a fluid bolus. Above all, anesthesiologists should acknowledge that fluid administration’s effects on a patient extend past the postanesthesia care unit, and the entire surgical team should be invested in the patient’s long-term recovery.

Our experience with ERAS

In 2011, Mayo Clinic was the first institution to implement enhanced recovery on a large scale in gynecologic surgery. We have subsequently made multiple pathway modifications in the spirit of continuous improvement (FIGURE 1).

For patients with ovarian cancer requiring extended procedures for cytoreduction via laparotomy (such as colon resection, splenectomy, diaphragm resection), enhanced recovery reduced the median hospital stay by 3 days, patient-controlled IV analgesia use by 88%, and postoperative opioid requirements by 90%.^9,10

At 48 hours after surgery, 40% of our patients require no opioids or tramadol, and epidurals are not utilized because of their effects on ambulation and the potential for hypotension. These reductions were met with stable to improved pain scores, a 60% decrease in nausea, and a 50% reduction in adynamic ileus.^9,10

Our initial efforts reduced 30-day costs of care by more than $850,000 in just 6 months, with savings of more than $7,600 for each patient undergoing a complex cytoreduction. Furthermore, these improvements allowed consolidation of our inpatient unit with those of other surgical specialties, serving higher volumes of patients within a smaller inpatient footprint. This contraction of inpatient services has accounted for an additional $1.1 million in savings every year since implementation (FIGURE 2).^9,10

Our group is not alone in realizing these benefits, and interest has intensified as demonstrated by the fact that the ERAS Society guidelines are among the all-time most downloaded articles in Gynecologic Oncology.^11,12 Although our research to demonstrate safety has focused on women undergoing complex oncologic operations, ERAS nevertheless hastens recovery, improves patient satisfaction, and adds value for all patients undergoing gynecologic surgery.

Continue to: Collateral improvements to practice...

Collateral improvements to practice

Clinical optimization using evidence-based practices such as enhanced recovery pathways can result in immediate patient benefit. Affecting such profound clinical improvements is energizing and creates a unique opportunity to transform the culture of the entire health care team. Irrespective of our provider roles (surgeon, anesthesiologist, nurse) or areas of interest (practice, research, education, leadership), we are united by a common purpose: to improve the human condition.¹³ Reaffirming this common purpose, through the collective effort involved in establishing a standardized enhanced recovery pathway, has allowed our practice and those of others to move beyond enhanced recovery and improve other areas of practice.

Other positive effects. The long-term collateral impact of this culture change at our institution is arguably more important than enhanced recovery itself. Examples of downstream impact include^14,15:

• 80% reduction in surgical site infection
• 50% reduction in anastomotic leaks
• 60% reduction in blood utilization for patients undergoing surgery for ovarian cancer.

Team-based pragmatic strategies. Additionally, our willingness to make decisions as a division rather than as individuals facilitated universal implementation of sentinel lymph node biopsy for patients with endometrial cancer and standardized imaging, testing, and surgical decision making for patients with ovarian and endometrial cancer.

The interventions associated with these improvements were not tested in a randomized fashion; however, rather than await perfect data, we made informed decisions based on imperfect data together with a commitment to continuous data review. We find this to be an effective strategy if our goal is to ensure that tomorrow’s outcomes will be better than yesterday’s. In this way, pragmatic trials can be extremely effective in rural settings and tertiary centers.

Barriers to innovation

The widely reported benefits of enhanced recovery beg the question, Why has enhanced recovery not been adopted universally as standard of care? The answer is multifaceted and highlights long-standing shortcomings in our health care system.

Most importantly, our health care system lacks a robust interface to link discovery of new techniques, treatments, and workflows to clinical practice. Perhaps the best example of this is the adoption of minimally invasive surgery (MIS) for endometrial cancer. Ten years have passed since randomized trials showed MIS has equivalent oncologic outcomes and superior recovery compared to laparotomy, yet in the United States less than 50% of women with endometrial cancer benefit.^16,17

However, even surgeons who are knowledgeable about recent innovations and genuinely wish to promote improvements may face near-insurmountable skepticism. Blind faith in our abilities and outcomes, overprotection of autonomy, close-mindedness, and satisfaction with the status quo are common responses to innovation and are the enemies of change. Resistance often comes from good intentions, but our desire to avoid complications may result in actions that could just as accurately be labeled superstitious as conservative. These observations suggest that developing methods to incorporate evidence-based practice into routine clinical use is the rate-limiting step in improving surgical quality.

Principles essential to change

Various methodologies have been described to manage change and facilitate implementation of new workflows and practices. Irrespective of the method used, including the more formal discipline of implementation science, at least 4 principles must be followed:

1. Teamwork. Mutual trust, mutual respect, and a sense of common purpose are minimum requirements for any successful initiative. Standardization is difficult or impossible without these elements. Thus, establishing a healthy team is the first step in implementing change.

2. Stakeholder analysis. Feedback from surgeons, nurses, residents, fellows, anesthesiologists, pharmacists, nurse anesthetists, and administrators is necessary to obtain diverse perspectives, facilitate engagement, and promote collaborative management. Negativity and resistance are common reactions to change, and it is particularly important to include those who are most skeptical in the stakeholder analysis to mitigate sabotage.

3. Concrete metrics. Success is possible only if defined a priori by specific and achievable goals. Counterbalances also are important to ensure that interventions do not have unintended consequences. Once a goal is met (for example, reduced hospital length of stay or costs), relevant metrics should be monitored after project completion for a minimum of 3 years to avoid regression to the pre-project state.

4. Leadership. The project champion responsible for the initiative must objectively facilitate all of the above and ensure excellent communication between stakeholders to nurture long-term engagement. Despite best efforts, if a minority of the group rejects compromise, this creates an opportunity to compare outcomes between those who do and do not accept the proposed change. Progress realized by early adopters may convince resistors to conform at a later time. Alternatively, the project champion also must have the insight to recognize when a proposed change is impossible at that point in time with that particular group. For example, our own initial attempts to implement enhanced recovery stalled in 2008, but they were successful 3 years later in a different environment.

Continue to: Although a discussion of leadership styles...

Although a discussion of leadership styles is beyond the scope of this article, in our experience, the most successful model is one of servant leadership that is team oriented rather than star dominated. Rather than being led by a single surgeon, each of the 4 quality improvement projects reviewed above (ERAS, and reductions in anastomotic leak, surgical site infection, and blood transfusion) that grew from enhanced recovery included trainees and was led by a different champion, encouraging teamwork and promoting career development. Such a model also supports the Accreditation Council for Graduate Medical Education’s emphasis on quality improvement education.

Physicians who have been sued multiple times are no more likely to relocate geographically than doctors who have never faced a claim, a new study shows.

David M. Studdert of Stanford (Calif.) University and his colleagues analyzed data from Medicare and the National Practitioner Data Bank (NPDB) to assess associations between the number of paid malpractice claims that doctors accrued and exits from medical practice, changes in clinical volume, geographic relocation, and change in practice-group size. The study population included 480,894 physicians who had 68,956 paid claims from 2003 to 2015. Of the study group, 89% had no claims, 9% had one claim, and the remaining 2% had two or more claims that accounted for 40% of all claims. Nearly three-quarters of the doctors studied were men, and the majority of specialties were internal medicine (17%), general practice/family medicine (15%), emergency medicine (7%), radiology (6%), and anesthesiology (6%).

Physicians with a higher number of claims against them did not relocate at a greater rate than physicians who had fewer or no claims, the investigators wrote in the New England Journal of Medicine.

More claims against a doctor were associated with a higher likelihood of leaving medicine and more shifts into smaller practice settings. For instance, physicians with one claim had 9% higher odds of leaving the practice than doctors with no claims, and physicians with five or more claims had a 45% higher chance of leaving medicine than doctors with no claims, the researchers found.

In addition, investigators found that doctors with two to four claims had 50%-60% higher odds of entering solo practice than physicians with no claims, and physicians with five or more claims had nearly 150% higher odds of moving to solo practice than doctors who had never been sued. Physicians with three or more claims were more likely to be male, work in surgical specialties, and be at least age 50 years.

The study addresses concerns that physicians with troubling legal records were moving across state lines for a fresh start, Mr. Studdert said in an interview. “We were surprised to find that physicians who accumulated multiple malpractice claims were no more likely to relocate their practices than physicians without claims. The National Practitioner Data Bank probably has something to do with that.”

Established by Congress in 1986, the NPDB was started, in part, to restrict the ability of incompetent physicians to move across states to hide their track records. By requiring hospitals to query doctors records before granting them clinical privileges and encouraging physician groups, health plans, and professional societies to do the same, the NPDB has “almost certainly increased the difficulty of relocation for physicians with legal problems,” the authors noted in the study.

A primary takeaway from the analysis is that, while a single malpractice claim is a relatively weak signal that a quality problem exists, multiple paid claims over a relatively short period of time are a strong signal that a physician may have a quality deficiency, Mr. Studdert said in the interview.

“Regulators and malpractice insurers should be paying closer attention to this signal,” he added. “To the extent that physicians are aware of a colleague’s checkered malpractice history, they may have a role to play too. Vigilance about signs of further problems, for one, but also careful thought about the wisdom of referring patients to such physicians.”

Michelle M. Mello, JD, PhD, and Mr. Studdert both reported receiving grants from SUMIT Insurance during the conduct of the study.

[email protected]

Source: Studdert DM et al. N Engl J Med. 2019 Mar 28. doi: 10.1056/NEJMsa1809981.

Physicians who have been sued multiple times are no more likely to relocate geographically than doctors who have never faced a claim, a new study shows.

David M. Studdert of Stanford (Calif.) University and his colleagues analyzed data from Medicare and the National Practitioner Data Bank (NPDB) to assess associations between the number of paid malpractice claims that doctors accrued and exits from medical practice, changes in clinical volume, geographic relocation, and change in practice-group size. The study population included 480,894 physicians who had 68,956 paid claims from 2003 to 2015. Of the study group, 89% had no claims, 9% had one claim, and the remaining 2% had two or more claims that accounted for 40% of all claims. Nearly three-quarters of the doctors studied were men, and the majority of specialties were internal medicine (17%), general practice/family medicine (15%), emergency medicine (7%), radiology (6%), and anesthesiology (6%).

Physicians with a higher number of claims against them did not relocate at a greater rate than physicians who had fewer or no claims, the investigators wrote in the New England Journal of Medicine.

More claims against a doctor were associated with a higher likelihood of leaving medicine and more shifts into smaller practice settings. For instance, physicians with one claim had 9% higher odds of leaving the practice than doctors with no claims, and physicians with five or more claims had a 45% higher chance of leaving medicine than doctors with no claims, the researchers found.

In addition, investigators found that doctors with two to four claims had 50%-60% higher odds of entering solo practice than physicians with no claims, and physicians with five or more claims had nearly 150% higher odds of moving to solo practice than doctors who had never been sued. Physicians with three or more claims were more likely to be male, work in surgical specialties, and be at least age 50 years.

The study addresses concerns that physicians with troubling legal records were moving across state lines for a fresh start, Mr. Studdert said in an interview. “We were surprised to find that physicians who accumulated multiple malpractice claims were no more likely to relocate their practices than physicians without claims. The National Practitioner Data Bank probably has something to do with that.”

Established by Congress in 1986, the NPDB was started, in part, to restrict the ability of incompetent physicians to move across states to hide their track records. By requiring hospitals to query doctors records before granting them clinical privileges and encouraging physician groups, health plans, and professional societies to do the same, the NPDB has “almost certainly increased the difficulty of relocation for physicians with legal problems,” the authors noted in the study.

A primary takeaway from the analysis is that, while a single malpractice claim is a relatively weak signal that a quality problem exists, multiple paid claims over a relatively short period of time are a strong signal that a physician may have a quality deficiency, Mr. Studdert said in the interview.

“Regulators and malpractice insurers should be paying closer attention to this signal,” he added. “To the extent that physicians are aware of a colleague’s checkered malpractice history, they may have a role to play too. Vigilance about signs of further problems, for one, but also careful thought about the wisdom of referring patients to such physicians.”

Michelle M. Mello, JD, PhD, and Mr. Studdert both reported receiving grants from SUMIT Insurance during the conduct of the study.

[email protected]

Source: Studdert DM et al. N Engl J Med. 2019 Mar 28. doi: 10.1056/NEJMsa1809981.

Physicians who have been sued multiple times are no more likely to relocate geographically than doctors who have never faced a claim, a new study shows.

David M. Studdert of Stanford (Calif.) University and his colleagues analyzed data from Medicare and the National Practitioner Data Bank (NPDB) to assess associations between the number of paid malpractice claims that doctors accrued and exits from medical practice, changes in clinical volume, geographic relocation, and change in practice-group size. The study population included 480,894 physicians who had 68,956 paid claims from 2003 to 2015. Of the study group, 89% had no claims, 9% had one claim, and the remaining 2% had two or more claims that accounted for 40% of all claims. Nearly three-quarters of the doctors studied were men, and the majority of specialties were internal medicine (17%), general practice/family medicine (15%), emergency medicine (7%), radiology (6%), and anesthesiology (6%).

Physicians with a higher number of claims against them did not relocate at a greater rate than physicians who had fewer or no claims, the investigators wrote in the New England Journal of Medicine.

More claims against a doctor were associated with a higher likelihood of leaving medicine and more shifts into smaller practice settings. For instance, physicians with one claim had 9% higher odds of leaving the practice than doctors with no claims, and physicians with five or more claims had a 45% higher chance of leaving medicine than doctors with no claims, the researchers found.

In addition, investigators found that doctors with two to four claims had 50%-60% higher odds of entering solo practice than physicians with no claims, and physicians with five or more claims had nearly 150% higher odds of moving to solo practice than doctors who had never been sued. Physicians with three or more claims were more likely to be male, work in surgical specialties, and be at least age 50 years.

The study addresses concerns that physicians with troubling legal records were moving across state lines for a fresh start, Mr. Studdert said in an interview. “We were surprised to find that physicians who accumulated multiple malpractice claims were no more likely to relocate their practices than physicians without claims. The National Practitioner Data Bank probably has something to do with that.”

Established by Congress in 1986, the NPDB was started, in part, to restrict the ability of incompetent physicians to move across states to hide their track records. By requiring hospitals to query doctors records before granting them clinical privileges and encouraging physician groups, health plans, and professional societies to do the same, the NPDB has “almost certainly increased the difficulty of relocation for physicians with legal problems,” the authors noted in the study.

A primary takeaway from the analysis is that, while a single malpractice claim is a relatively weak signal that a quality problem exists, multiple paid claims over a relatively short period of time are a strong signal that a physician may have a quality deficiency, Mr. Studdert said in the interview.

“Regulators and malpractice insurers should be paying closer attention to this signal,” he added. “To the extent that physicians are aware of a colleague’s checkered malpractice history, they may have a role to play too. Vigilance about signs of further problems, for one, but also careful thought about the wisdom of referring patients to such physicians.”

Michelle M. Mello, JD, PhD, and Mr. Studdert both reported receiving grants from SUMIT Insurance during the conduct of the study.

[email protected]

Source: Studdert DM et al. N Engl J Med. 2019 Mar 28. doi: 10.1056/NEJMsa1809981.

WASHINGTON – A program combining loan repayment and scholarships could encourage more medical students to pursue primary care upon graduation, according to a proposal presented at a meeting of the Medicare Payment Advisory Commission.

“A Medicare[-based] program would have a specific objective to encourage more physicians to enter primary care and provide primary care to beneficiaries,” MedPAC staffer Ariel Winter said. “By reducing educational debt, a Medicare-specific program would provide a financial incentive for physicians to choose primary care.”

Any program would face some challenges, Mr. Winter noted. Based on evidence, “it’s difficult to predict how physicians would respond if they were offered debt reduction in exchange for a commitment to practice primary care,” as financial considerations are not the only reason why physicians choose a specific career track.

Financing the program would also need to be considered. MedPAC staff recommended using a separate recommendation, one to end the Merit-based Incentive Payment System and use its $500 million put aside as MIPS bonuses to pay for any Medicare-based program.

Staff proposed a pilot program to “test the impact of different design choices on program operations, physician participation, and career choices,” he said. “Policymakers could use the results to improve the program and decide whether to expand it.”

MedPAC Vice Chairman Jon Christianson, PhD, suggested any program be tied to “physicians who practiced in areas where Medicare beneficiaries don’t have adequate access” to primary care doctors.

However, Mr. Winter noted that he is not aware of “any off-the-shelf system that identifies areas where there’s a problem, where there’s a shortage of clinicians for Medicare beneficiaries specifically. I am not sure how you would do that.”

MedPAC member Kathy Buto, former vice president of global health policy at Johnson & Johnson, questioned whether nurse practitioners and physician assistants should be included in the program, as they “are beginning to subspecialize and get out of primary care.” Mr. Winter said it is open for consideration.

MedPAC member Pat Wang, president and CEO of Healthfirst in New York, questioned whether a new program was needed or whether fixing of existing programs, “making them work better” is the way to go given the evidence that the effect of student debt on decision making is mixed.

She suggested that rather than targeting loan forgiveness, maybe the program should be structured more as a bonus payment rather than debt forgiveness as a means of incentivizing people who may not be concerned with debt forgiveness.

Ms. Buto added that questions of autonomy might also need to be addressed. “Physicians often feel like they don’t have control in Medicare, that they’re required to do a lot of things, and that they are subject to the fee schedule. If there were some way to grant more autonomy, control, and convey status that way, whether it has to do with greater flexibility in whatever, payment models and so on, that’s where I think you can begin to shift the status within primary care.”

MedPAC Chairman Francis Crosson, MD, recalled his time at Kaiser Permanente and noted their programs showed success because of the combination of a significant amount of money and time commitment (10 years).

The time commitment became an important part because after that long, physicians became a part of their communities and tended to stay.

“Two or 3 years, from my perspective and my experience, doesn’t work very well,” Dr. Crosson said. “But a significant period of time does, and a significant amount of money does seem to work.”

[email protected]

WASHINGTON – A program combining loan repayment and scholarships could encourage more medical students to pursue primary care upon graduation, according to a proposal presented at a meeting of the Medicare Payment Advisory Commission.

“A Medicare[-based] program would have a specific objective to encourage more physicians to enter primary care and provide primary care to beneficiaries,” MedPAC staffer Ariel Winter said. “By reducing educational debt, a Medicare-specific program would provide a financial incentive for physicians to choose primary care.”

Any program would face some challenges, Mr. Winter noted. Based on evidence, “it’s difficult to predict how physicians would respond if they were offered debt reduction in exchange for a commitment to practice primary care,” as financial considerations are not the only reason why physicians choose a specific career track.

Financing the program would also need to be considered. MedPAC staff recommended using a separate recommendation, one to end the Merit-based Incentive Payment System and use its $500 million put aside as MIPS bonuses to pay for any Medicare-based program.

Staff proposed a pilot program to “test the impact of different design choices on program operations, physician participation, and career choices,” he said. “Policymakers could use the results to improve the program and decide whether to expand it.”

MedPAC Vice Chairman Jon Christianson, PhD, suggested any program be tied to “physicians who practiced in areas where Medicare beneficiaries don’t have adequate access” to primary care doctors.

However, Mr. Winter noted that he is not aware of “any off-the-shelf system that identifies areas where there’s a problem, where there’s a shortage of clinicians for Medicare beneficiaries specifically. I am not sure how you would do that.”

MedPAC member Kathy Buto, former vice president of global health policy at Johnson & Johnson, questioned whether nurse practitioners and physician assistants should be included in the program, as they “are beginning to subspecialize and get out of primary care.” Mr. Winter said it is open for consideration.

MedPAC member Pat Wang, president and CEO of Healthfirst in New York, questioned whether a new program was needed or whether fixing of existing programs, “making them work better” is the way to go given the evidence that the effect of student debt on decision making is mixed.

She suggested that rather than targeting loan forgiveness, maybe the program should be structured more as a bonus payment rather than debt forgiveness as a means of incentivizing people who may not be concerned with debt forgiveness.

Ms. Buto added that questions of autonomy might also need to be addressed. “Physicians often feel like they don’t have control in Medicare, that they’re required to do a lot of things, and that they are subject to the fee schedule. If there were some way to grant more autonomy, control, and convey status that way, whether it has to do with greater flexibility in whatever, payment models and so on, that’s where I think you can begin to shift the status within primary care.”

MedPAC Chairman Francis Crosson, MD, recalled his time at Kaiser Permanente and noted their programs showed success because of the combination of a significant amount of money and time commitment (10 years).

The time commitment became an important part because after that long, physicians became a part of their communities and tended to stay.

“Two or 3 years, from my perspective and my experience, doesn’t work very well,” Dr. Crosson said. “But a significant period of time does, and a significant amount of money does seem to work.”

[email protected]

WASHINGTON – A program combining loan repayment and scholarships could encourage more medical students to pursue primary care upon graduation, according to a proposal presented at a meeting of the Medicare Payment Advisory Commission.

“A Medicare[-based] program would have a specific objective to encourage more physicians to enter primary care and provide primary care to beneficiaries,” MedPAC staffer Ariel Winter said. “By reducing educational debt, a Medicare-specific program would provide a financial incentive for physicians to choose primary care.”

Any program would face some challenges, Mr. Winter noted. Based on evidence, “it’s difficult to predict how physicians would respond if they were offered debt reduction in exchange for a commitment to practice primary care,” as financial considerations are not the only reason why physicians choose a specific career track.

Financing the program would also need to be considered. MedPAC staff recommended using a separate recommendation, one to end the Merit-based Incentive Payment System and use its $500 million put aside as MIPS bonuses to pay for any Medicare-based program.

Staff proposed a pilot program to “test the impact of different design choices on program operations, physician participation, and career choices,” he said. “Policymakers could use the results to improve the program and decide whether to expand it.”

MedPAC Vice Chairman Jon Christianson, PhD, suggested any program be tied to “physicians who practiced in areas where Medicare beneficiaries don’t have adequate access” to primary care doctors.

However, Mr. Winter noted that he is not aware of “any off-the-shelf system that identifies areas where there’s a problem, where there’s a shortage of clinicians for Medicare beneficiaries specifically. I am not sure how you would do that.”

MedPAC member Kathy Buto, former vice president of global health policy at Johnson & Johnson, questioned whether nurse practitioners and physician assistants should be included in the program, as they “are beginning to subspecialize and get out of primary care.” Mr. Winter said it is open for consideration.

MedPAC member Pat Wang, president and CEO of Healthfirst in New York, questioned whether a new program was needed or whether fixing of existing programs, “making them work better” is the way to go given the evidence that the effect of student debt on decision making is mixed.

She suggested that rather than targeting loan forgiveness, maybe the program should be structured more as a bonus payment rather than debt forgiveness as a means of incentivizing people who may not be concerned with debt forgiveness.

Ms. Buto added that questions of autonomy might also need to be addressed. “Physicians often feel like they don’t have control in Medicare, that they’re required to do a lot of things, and that they are subject to the fee schedule. If there were some way to grant more autonomy, control, and convey status that way, whether it has to do with greater flexibility in whatever, payment models and so on, that’s where I think you can begin to shift the status within primary care.”

MedPAC Chairman Francis Crosson, MD, recalled his time at Kaiser Permanente and noted their programs showed success because of the combination of a significant amount of money and time commitment (10 years).

The time commitment became an important part because after that long, physicians became a part of their communities and tended to stay.

“Two or 3 years, from my perspective and my experience, doesn’t work very well,” Dr. Crosson said. “But a significant period of time does, and a significant amount of money does seem to work.”

[email protected]

WASHINGTON – Although list prices remain an easy target when discussing spikes in insulin prices, reforms are needed across the supply chain for the problem to be fully resolved, panelists said at a House Committee on Energy & Commerce hearing on insulin affordability.

“Each member of the supply chain has a responsibility to help solve this problem,” said Alvin C. Powers, MD, director of the Vanderbilt Diabetes Center at Vanderbilt University, who was speaking on behalf of the Endocrine Society during the April 2 hearing of the committee’s oversight & investigations subcommittee.

Dr. Powers identified all members – manufacturers, payers, pharmacy benefit managers, patients, providers, and Congress – as having a role in developing a solution that will encourage more access to the treatment.

The hearing was the first of two in a series specifically examining the price of insulin. This one focused on the role pricing issues play in terms of access to insulin and patient outcomes.

To highlight the pricing issues, it was noted that a vial of Humalog (insulin lispro) cost $21 when it was launched by Eli Lilly in 1996. It now costs $275 even though it has gone through no changes in formulation or innovation during that time.

Kasia Lipska, MD, of Yale University School of Medicine noted that a summer 2017 survey conducted by the Yale Diabetes Center found that one in four patients took less than the prescribed dose of insulin specifically because of the cost of insulin.

[email protected]

WASHINGTON – Although list prices remain an easy target when discussing spikes in insulin prices, reforms are needed across the supply chain for the problem to be fully resolved, panelists said at a House Committee on Energy & Commerce hearing on insulin affordability.

“Each member of the supply chain has a responsibility to help solve this problem,” said Alvin C. Powers, MD, director of the Vanderbilt Diabetes Center at Vanderbilt University, who was speaking on behalf of the Endocrine Society during the April 2 hearing of the committee’s oversight & investigations subcommittee.

Dr. Powers identified all members – manufacturers, payers, pharmacy benefit managers, patients, providers, and Congress – as having a role in developing a solution that will encourage more access to the treatment.

The hearing was the first of two in a series specifically examining the price of insulin. This one focused on the role pricing issues play in terms of access to insulin and patient outcomes.

To highlight the pricing issues, it was noted that a vial of Humalog (insulin lispro) cost $21 when it was launched by Eli Lilly in 1996. It now costs $275 even though it has gone through no changes in formulation or innovation during that time.

Kasia Lipska, MD, of Yale University School of Medicine noted that a summer 2017 survey conducted by the Yale Diabetes Center found that one in four patients took less than the prescribed dose of insulin specifically because of the cost of insulin.

[email protected]

WASHINGTON – Although list prices remain an easy target when discussing spikes in insulin prices, reforms are needed across the supply chain for the problem to be fully resolved, panelists said at a House Committee on Energy & Commerce hearing on insulin affordability.

“Each member of the supply chain has a responsibility to help solve this problem,” said Alvin C. Powers, MD, director of the Vanderbilt Diabetes Center at Vanderbilt University, who was speaking on behalf of the Endocrine Society during the April 2 hearing of the committee’s oversight & investigations subcommittee.

Dr. Powers identified all members – manufacturers, payers, pharmacy benefit managers, patients, providers, and Congress – as having a role in developing a solution that will encourage more access to the treatment.

The hearing was the first of two in a series specifically examining the price of insulin. This one focused on the role pricing issues play in terms of access to insulin and patient outcomes.

To highlight the pricing issues, it was noted that a vial of Humalog (insulin lispro) cost $21 when it was launched by Eli Lilly in 1996. It now costs $275 even though it has gone through no changes in formulation or innovation during that time.

Kasia Lipska, MD, of Yale University School of Medicine noted that a summer 2017 survey conducted by the Yale Diabetes Center found that one in four patients took less than the prescribed dose of insulin specifically because of the cost of insulin.

[email protected]

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

Join us Wednesday, April 3, 2019, at 6:00 pm EST, for a Twitter discussion on caring for LGBT youth. Two pediatricians that are passionate about the LGBT community and children will be joining the conversation: Dr. Gayathri Chelvakumar and Dr. Gerald T. Montano.

Questions will include:

• How do people become aware they are gay, lesbian, bisexual, or transgender?
• How can we address specific health concerns of LGBT youth?
• How can we make our practices a safe space for LGBT youth?
• What is gender dysphoria, and how is it treated?

LGBT Youth Consult, by Dr. Gayathri Chelvakumar

• A primer on sexuality and gender identity
• Creating safe spaces for LGBTQ youth, families in health care settings
• How we can support our LGBTQ patients
• New research on health-related behaviors of sexual minority youth
• Promoting mental well-being in LGBTQ youth

New to Twitter Chats? Steps to join the conversation are below.

Join us Wednesday, April 3, 2019, at 6:00 pm EST, for a Twitter discussion on caring for LGBT youth. Two pediatricians that are passionate about the LGBT community and children will be joining the conversation: Dr. Gayathri Chelvakumar and Dr. Gerald T. Montano.

Questions will include:

• How do people become aware they are gay, lesbian, bisexual, or transgender?
• How can we address specific health concerns of LGBT youth?
• How can we make our practices a safe space for LGBT youth?
• What is gender dysphoria, and how is it treated?

LGBT Youth Consult, by Dr. Gayathri Chelvakumar

• A primer on sexuality and gender identity
• Creating safe spaces for LGBTQ youth, families in health care settings
• How we can support our LGBTQ patients
• New research on health-related behaviors of sexual minority youth
• Promoting mental well-being in LGBTQ youth

New to Twitter Chats? Steps to join the conversation are below.

Join us Wednesday, April 3, 2019, at 6:00 pm EST, for a Twitter discussion on caring for LGBT youth. Two pediatricians that are passionate about the LGBT community and children will be joining the conversation: Dr. Gayathri Chelvakumar and Dr. Gerald T. Montano.

Questions will include:

• How do people become aware they are gay, lesbian, bisexual, or transgender?
• How can we address specific health concerns of LGBT youth?
• How can we make our practices a safe space for LGBT youth?
• What is gender dysphoria, and how is it treated?

LGBT Youth Consult, by Dr. Gayathri Chelvakumar

• A primer on sexuality and gender identity
• Creating safe spaces for LGBTQ youth, families in health care settings
• How we can support our LGBTQ patients
• New research on health-related behaviors of sexual minority youth
• Promoting mental well-being in LGBTQ youth

New to Twitter Chats? Steps to join the conversation are below.

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

[email protected]

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

[email protected]

ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.

The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.

The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.

The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.

Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.

“Most patients who have responded continue on drug,” he said in a video interview.

Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.

“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”

[email protected]

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

Prenatal diagnosis of genetic anomalies is important for diagnosing lethal genetic conditions before birth. It can provide information for parents regarding pregnancy options and allow for recurrence risk counseling and the potential use of preimplantation genetic testing in the next pregnancy. For decades, a karyotype was used to analyze amniocentesis and chorionic villus sampling specimens; in recent years, chromosomal microarray analysis provides more information about significant chromosomal abnormalities, including microdeletions and microduplications. However, microarrays also have limitations, as they do not identify base pair changes associated with single-gene disorders.

The advent of next-generation sequencing has substantially reduced the cost of DNA sequencing. Whole genome sequencing (WGS) can sequence the entire genome— both the coding (exonic) and noncoding (intronic) regions—while exome sequencing analyzes only the protein-coding exons, which make up 1% to 2% of the genome and about 85% of the protein-coding genes associated with known human disease. Exome sequencing increasingly is used in cases of suspected genetic disorders when other tests have been unrevealing.

In this Update, we review recent reports of prenatal exome sequencing, including studies exploring the yield in fetuses with structural anomalies; the importance of prenatal phenotyping; the perspectives of parents and health care professionals who were involved in prenatal exome sequencing studies; and a summary of a joint position statement from 3 societies regarding prenatal sequencing.

Prenatal whole exome sequencing has potential utility, with some limitations 

Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758-767. 
 

Lord J, McMullan DJ, Eberhardt RY, et al; for the Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747-757. 

Exome sequencing has been shown to identify an underlying genetic cause in 25% to 30% of children with an undiagnosed suspected genetic disorder. Two studies recently published in the Lancet sought to determine the incremental diagnostic yield of prenatal whole exome sequencing (WES) in the setting of fetal structural anomalies when karyotype and microarray results were normal. 

Continue to: Details of the studies...

In a prospective cohort study by Petrovski and colleagues, DNA samples from 234 fetuses with a structural anomaly (identified on ultrasonography) and both parents (parent-fetus "trios") were used for analysis. WES identified diagnostic genetic variants in 24 trios (10%). An additional 46 (20%) had variants that indicated pathogenicity but without sufficient evidence to be considered diagnostic. 

The anomalies with the highest frequency of a genetic diagnosis were lymphatic, 24%; skeletal, 24%; central nervous system, 22%; and renal, 16%; while cardiac anomalies had the lowest yield at 5%. 

In another prospective cohort study, known as the Prenatal Assessment of Genomes and Exomes (PAGE), Lord and colleagues sequenced DNA samples from 610 parent-fetus trios, but they restricted sequencing to a predefined list of 1,628 genes. Diagnostic genetic variants were identified in 52 fetuses (8.5%), while 24 (3.9%) had a variant of uncertain significance that was thought to be of potential clinical usefulness. 

Fetuses with multiple anomalies had the highest genetic yield (15.4%), followed by skeletal (15.4%) and cardiac anomalies (11.1%), with the lowest yield in fetuses with isolated increased nuchal translucency (3.2%). 

Diagnostic yield is high, but prenatal utility is limited 

Both studies showed a clinically significant diagnostic yield of 8% to 10% for prenatal exome sequencing in cases of fetal structural anomalies with normal karyotype and microarray testing. While this yield demonstrates the utility of prenatal exome sequencing, it is significantly lower than what has been reported in postnatal studies. One of the reasons for this is the inherent limitation of prenatal phenotyping (discussed below). 

The importance of prenatal phenotyping 

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181. 

In postnatal exome sequencing, the physical exam, imaging findings, and laboratory results are components of the phenotype that are used to interpret the sequencing data. Prenatal phenotyping, however, is limited to the use of fetal ultrasonography and, occasionally, the addition of magnetic resonance imaging. Prenatal phenotyping is without the benefit of an exam to detect more subtle anomalies or functional status, such as developmental delay, seizures, or failure to thrive. 

When a structural anomaly is identified on prenatal ultrasonography, it is especially important that detailed imaging be undertaken to detect other anomalies, including more subtle facial features and dysmorphology. 

Value of reanalyzing exome sequencing data 

Aarabi and colleagues conducted a retrospective study of 20 fetuses with structural anomalies and normal karyotype and microarray. They performed trio exome sequencing first using information available only prenatally and then conducted a reanalysis using information available after delivery. 

With prenatal phenotyping only, the investigators identified no pathogenic, or likely pathogenic, variants. On reanalysis of combined prenatal and postnatal findings, however, they identified pathogenic variants in 20% of cases. 

Significance of the findings 

This study highlights both the importance of a careful, detailed fetal ultrasonography study and the possible additional benefit of a postnatal examination (such as an autopsy) in order to yield improved results. In addition, the authors noted that the development of a prenatal phenotype-genotype database would significantly help exome sequencing interpretation in the prenatal setting.

Social impact of WES: Parent and provider perspectives 

Wou K, Weitz T, McCormack C, et al. Parental perceptions of prenatal whole exome sequencing (PPPWES) study. Prenat Diagn. 2018;38:801-811. 

Horn R, Parker M. Health professionals' and researchers' perspectives on prenatal whole genome and exome sequencing: 'We can't shut the door now, the genie's out, we need to refine it.' PLoS One. 2018;13:e0204158. 

As health care providers enter a new era of prenatal genetic testing with exome sequencing, it is crucial to the path forward that we obtain perspectives from the parents and providers who participated in these studies. Notably, in both of the previously discussed Lancet reports, the authors interviewed the participants to discuss the challenges involved and identify strategies for improving future testing. 

Continue to: What parents want...

To ascertain the perceptions of couples who underwent prenatal WES, Wou and colleagues conducted semi-structured interviews with participants from the Fetal Sequencing Study regarding their experience. They interviewed 29 parents from 17 pregnancies, including a mix of those who had pathogenic prenatal results, terminated prior to receiving the results, and had normal results. 
 

Expressed feelings and desires. Parents recalled feelings of anxiety and stress around the time of diagnosis and the need for help with coping while awaiting results. The majority of parents reported that they would like to be told about uncertain results, but that desire decreased as the certainty of results decreased. 

Parents were overall satisfied with the prenatal genetic testing experience, but they added that they would have liked to receive written materials beforehand and a written report of the test results (including negative cases). They also would like to have connected with other families with similar experiences, to have received results sooner, and to have an in-person meeting after telephone disclosure of the results. 

Health professionals articulate complexity of prenatal genomics 

In a qualitative interview study to explore critical issues involved in the clinical practice use of prenatal genomics, Horn and Parker conducted interviews with 20 health care professionals who were involved in the previously described PAGE trial. Patient recruiters, midwives, genetic counselors, research assistants, and laboratory staff were included. 

Interviewees cited numerous challenges involved in their day-to-day work with prenatal whole genome and exome sequencing, including: 

• the complexity of achieving valid parental consent at a time of vulnerability 
• management of parent expectations  
• transmitting and comprehending complex information 
• the usefulness of information 
• the difficulty of a long turnaround time for study results. 

All the interviewees agreed that prenatal exome sequencing studies contribute to knowledge generation and the advancement of technology. 

The authors concluded that an appropriate next step would be the development of appropriate guidelines for good ethical practice that address the concerns encountered in genomics clinical practice.

Societies offer guidance on using genome and exome sequencing 

International Society for Prenatal Diagnosis, Society for Maternal and Fetal Medicine, Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018;38:6-9. 

In response to the rapid integration of exome sequencing for genetic diagnosis, several professional societies—the International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, and Perinatal Quality Foundation—issued a joint statement addressing the clinical use of prenatal diagnostic genome wide sequencing, including exome sequencing. 

Continue to: Guidance at a glance...

The societies' recommendations are summarized as follows: 

• Exome sequencing is best done as a trio analysis, with fetal and both parental samples sequenced and analyzed together. 
• Extensive pretest education, counseling, and informed consent, as well as posttest counseling, are essential. This should include:  

—the types of results to be conveyed (variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign) 
—the possibility that results will not be obtained or may not be available before the birth of the fetus 
—realistic expectations regarding the likelihood that a significant result will be obtained 
—the timeframe to results 
—the option to include or exclude in the results incidental or secondary findings (such as an unexpected childhood disorder, cancer susceptibility genes, adult-onset disorders) 
—the possibility of uncovering nonpaternity or consanguinity 
—the potential reanalysis of results over time 
—how data are stored, who has access, and for what purpose. 

• Fetal sequencing may be beneficial in the following scenarios: 

—multiple fetal anomalies or a single major anomaly suggestive of a genetic disorder, when the microarray is negative 
—no microarray result is available, but the fetus exhibits a pattern of anomalies strongly suggestive of a single-gene disorder  
—a prior undiagnosed fetus (or child) with anomalies suggestive of a genetic etiology, and with similar anomalies in the current pregnancy, with normal karyotype or microarray. Providers also can consider sequencing samples from both parents prior to preimplantation genetic testing to check for shared carrier status for autosomal recessive mutations, although obtaining exome sequencing from the prior affected fetus (or child) is ideal. 
—history of recurrent stillbirths of unknown etiology, with a recurrent pattern of anomalies in the current pregnancy, with normal karyotype or microarray. 

• Interpretation of results should be done using a multidisciplinary team-based approach, including clinical scientists, geneticists, genetic counselors, and experts in prenatal diagnosis. 
• Where possible and after informed consent, reanalysis of results should be undertaken if a future pregnancy is planned or ongoing, and a significant amount of time has elapsed since the time the result was last reported. 
• Parents should be given a written report of test results. 

Summary

Exome sequencing is increasingly becoming mainstream in postnatal genetic testing, and it is emerging as the newest diagnostic frontier in prenatal genetic testing. However, there are limitations to prenatal exome sequencing, including issues with consent at a vulnerable time for parents, limited information available regarding the phenotype, and results that may not be available before the birth of a fetus. Providers should be familiar with the indications for testing, the possible results, the limitations of prenatal phenotyping, and the implications for future pregnancies. 
 

EXPERT COMMENTARY

Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019;364:1665.

Alzheimer disease represents the most common cause of dementia. Although sex hormones may play a role in the etiology of AD in women, studies addressing the impact of menopausal HT on risk of AD have conflicting findings.

Finnish researchers Savolainen-Peltonen and colleagues aimed to compare postmenopausal HT use in women with and without AD. They used national drug and population registries to identify patients with AD, control women without a diagnosis of AD, and data on postmenopausal HT use.

Details of the study

In Finland, reimbursement for treatment related to AD requires cognitive testing, brain imaging, and a statement from a specialist physician. Using national records, the study investigators identified 84,739 women with a diagnosis of AD during the years 1999–2013 and the same number of control women (without AD) during the same period. A national drug reimbursement registry was used to identify HT use from the year 1994.

Findings. Women diagnosed with AD were more likely to have been current or former users of systemic HT than controls (18.6% vs 17.0%, P<.001). The odds ratios (ORs) for AD were 1.09 for the estradiol-only group and 1.17 for the estrogen-progestin group (P<.05 for both comparisons).

Initiation of HT prior to age 60 was less common among AD cases than controls (P = .006). As a continuous variable, age was not a determinant for disease risk in estradiol-only users (OR, 1.0), estrogen-progestin users (OR, 1.0), or any HT use (OR, 1.0).

The exclusive use of vaginal estrogen therapy was not associated with an elevated risk of AD (OR, 0.99).

Study strengths and limitations

This study on the association between HT and AD included a very large number of participants from a national population registry, and the use of HT was objectively determined from a controlled registry (not self-reported). In addition, AD was accurately diagnosed and differentiated from other forms of dementia.

Limitations of the study include the lack of baseline demographic data for AD risk factors for both HT users and controls. Further, an increased risk of AD may have been a cause for HT use and not a consequence, given that initial cognitive impairments may occur 7 to 8 years prior to AD diagnosis and the possibility exists that such women may have sought help for cognitive symptoms from HT. In addition, the lack of brain imaging or neurologic examination to exclude AD might also account for undiagnosed disease in controls. The authors noted that they were unable to compare the use of oral and transdermal HT preparations or the use of cyclic and continuous estrogen-progestin therapy.

EXPERT COMMENTARY

Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019;364:1665.

Alzheimer disease represents the most common cause of dementia. Although sex hormones may play a role in the etiology of AD in women, studies addressing the impact of menopausal HT on risk of AD have conflicting findings.

Finnish researchers Savolainen-Peltonen and colleagues aimed to compare postmenopausal HT use in women with and without AD. They used national drug and population registries to identify patients with AD, control women without a diagnosis of AD, and data on postmenopausal HT use.

Details of the study

In Finland, reimbursement for treatment related to AD requires cognitive testing, brain imaging, and a statement from a specialist physician. Using national records, the study investigators identified 84,739 women with a diagnosis of AD during the years 1999–2013 and the same number of control women (without AD) during the same period. A national drug reimbursement registry was used to identify HT use from the year 1994.

Findings. Women diagnosed with AD were more likely to have been current or former users of systemic HT than controls (18.6% vs 17.0%, P<.001). The odds ratios (ORs) for AD were 1.09 for the estradiol-only group and 1.17 for the estrogen-progestin group (P<.05 for both comparisons).

Initiation of HT prior to age 60 was less common among AD cases than controls (P = .006). As a continuous variable, age was not a determinant for disease risk in estradiol-only users (OR, 1.0), estrogen-progestin users (OR, 1.0), or any HT use (OR, 1.0).

The exclusive use of vaginal estrogen therapy was not associated with an elevated risk of AD (OR, 0.99).

Study strengths and limitations

This study on the association between HT and AD included a very large number of participants from a national population registry, and the use of HT was objectively determined from a controlled registry (not self-reported). In addition, AD was accurately diagnosed and differentiated from other forms of dementia.

Limitations of the study include the lack of baseline demographic data for AD risk factors for both HT users and controls. Further, an increased risk of AD may have been a cause for HT use and not a consequence, given that initial cognitive impairments may occur 7 to 8 years prior to AD diagnosis and the possibility exists that such women may have sought help for cognitive symptoms from HT. In addition, the lack of brain imaging or neurologic examination to exclude AD might also account for undiagnosed disease in controls. The authors noted that they were unable to compare the use of oral and transdermal HT preparations or the use of cyclic and continuous estrogen-progestin therapy.

EXPERT COMMENTARY

Savolainen-Peltonen H, Rahkola-Soisalo P, Hoti F, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study. BMJ. 2019;364:1665.

Alzheimer disease represents the most common cause of dementia. Although sex hormones may play a role in the etiology of AD in women, studies addressing the impact of menopausal HT on risk of AD have conflicting findings.

Finnish researchers Savolainen-Peltonen and colleagues aimed to compare postmenopausal HT use in women with and without AD. They used national drug and population registries to identify patients with AD, control women without a diagnosis of AD, and data on postmenopausal HT use.

Details of the study

In Finland, reimbursement for treatment related to AD requires cognitive testing, brain imaging, and a statement from a specialist physician. Using national records, the study investigators identified 84,739 women with a diagnosis of AD during the years 1999–2013 and the same number of control women (without AD) during the same period. A national drug reimbursement registry was used to identify HT use from the year 1994.

Findings. Women diagnosed with AD were more likely to have been current or former users of systemic HT than controls (18.6% vs 17.0%, P<.001). The odds ratios (ORs) for AD were 1.09 for the estradiol-only group and 1.17 for the estrogen-progestin group (P<.05 for both comparisons).

Initiation of HT prior to age 60 was less common among AD cases than controls (P = .006). As a continuous variable, age was not a determinant for disease risk in estradiol-only users (OR, 1.0), estrogen-progestin users (OR, 1.0), or any HT use (OR, 1.0).

The exclusive use of vaginal estrogen therapy was not associated with an elevated risk of AD (OR, 0.99).

Study strengths and limitations

This study on the association between HT and AD included a very large number of participants from a national population registry, and the use of HT was objectively determined from a controlled registry (not self-reported). In addition, AD was accurately diagnosed and differentiated from other forms of dementia.

Limitations of the study include the lack of baseline demographic data for AD risk factors for both HT users and controls. Further, an increased risk of AD may have been a cause for HT use and not a consequence, given that initial cognitive impairments may occur 7 to 8 years prior to AD diagnosis and the possibility exists that such women may have sought help for cognitive symptoms from HT. In addition, the lack of brain imaging or neurologic examination to exclude AD might also account for undiagnosed disease in controls. The authors noted that they were unable to compare the use of oral and transdermal HT preparations or the use of cyclic and continuous estrogen-progestin therapy.