Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.

SAN DIEGO – Readmission rates and the underlying reasons for them vary between medical specialties following surgery in children, a study of national data suggests.

“Hospital readmission is a very hot topic, particularly in light of the Affordable Care Act,” Afif N. Kulaylat, MD, said at the American College of Surgeons/National Surgical Quality Improvement Program National Conference. “Beyond economic costs there are very tangible costs to patients that we must consider. Readmissions have been associated with significant morbidity for patients. They often herald or implicate a postoperative complication. There are also indirect costs to patients and families such as time off from school or work.”

Dr. Kulaylat, of the division of pediatric surgery at Penn State Children’s Hospital, Hershey, Penn., presented findings from a retrospective analysis of NSQIP Pediatric (NSQIP-P), an ongoing collaboration between the ACS and the American Pediatric Surgical Association to improve the care of young patients. The researchers evaluated NSQIP-P data from 2013 and 2014 and focused on unplanned readmission within 30 days, including reasons for readmission based on NSQIP-P readmission categories and ICD-9 readmission codes as categorized by the AHRQ Clinical Classification Software. Multivariate logistic regression was used to evaluate factors associated with unplanned readmission.

Dr. Kulaylat reported results from a cohort of 129,849 patients cared for by 64 NSQIP-P participating hospitals. Among these, the all-cause readmission rate was 4.7%. After excluding patients with planned readmissions, the unplanned readmission rate was found to be 3.9%. From this cohort, 28% required reoperation within 30 days, and the median time from discharge to unplanned readmission was 8 days, with an interquartile range between 3 and 14 days.

Among the procedures captured in NSQIP-P, neurosurgery accounted for the highest readmission rate (10.8%), followed by general/thoracic surgery (5.2%), urology (2.6%), ENT (2%), orthopedic (1.9%), and plastic and reconstructive surgery (1.3%). The most common reason for readmission was surgical site infection at 23%, followed by GI complications such as ileus, obstruction, and constipation (17%); pulmonary-related complications (9%); device-related complications including shunt malfunction (8%); neurologic (7%); pain (6%); other medical diseases (6%); sepsis (5%); electrolytes/dehydration (5%); and urinary tract infection (UTI, 3%). It is estimated that at least two-thirds of unplanned readmissions (63%) were directly related to surgery. “These reasons for readmission and their frequency closely parallel what is seen in adults, with the exception of bleeding complications, which were rare in children compared to adults,” Dr. Kulaylat said.

The top five CPT codes associated with readmissions were laparoscopic appendectomy, laparoscopic gastrostomy tube placement, and three additional codes related to placement and replacement/revision of ventricular shunts/catheters.

Reasons for readmission varied among specialties. For example, among general and thoracic surgery, surgical-site infections (SSI) and GI-related issues dominated, while in neurosurgery SSI and device issues dominated. In urology, UTIs were the most frequent, while ENT had a greater proportion of pulmonary complications. Certain patient variables were also associated with an increased risk of hospital readmission, including comorbidities related to GI, CNS, renal, and immunosuppression and nutrition (P less than .001 for all). The strongest association was the occurrence of a postoperative complication, namely a post-discharge complication.

“The granularity of NSQIP-P can continue to be refined to help predict who is likely to get readmitted or if specific follow-up strategies might identify those headed to readmission,” remarked Robert E. Cilley, MD, a senior author and surgeon-in-chief at Penn State Children’s Hospital. Dr. Kulaylat acknowledged certain limitations of the study, including its retrospective design, the potential for data entry/data interpretation error, and that the researchers were unable to adjust for clustering at the hospital level. Directions of future research include a plan to study readmissions and predictive factors at the procedural level, establish risk-adjusted specialty/procedural-specific benchmarks for readmission rates, and refine the accuracy and reliability of the readmission data. “With these NSQIP-P data there is substantial opportunity for quality improvement as we strive to improve the care of children everywhere,” Dr. Kulaylat said. He reported having no relevant disclosures.

[email protected]

SAN DIEGO – Readmission rates and the underlying reasons for them vary between medical specialties following surgery in children, a study of national data suggests.

“Hospital readmission is a very hot topic, particularly in light of the Affordable Care Act,” Afif N. Kulaylat, MD, said at the American College of Surgeons/National Surgical Quality Improvement Program National Conference. “Beyond economic costs there are very tangible costs to patients that we must consider. Readmissions have been associated with significant morbidity for patients. They often herald or implicate a postoperative complication. There are also indirect costs to patients and families such as time off from school or work.”

Dr. Kulaylat, of the division of pediatric surgery at Penn State Children’s Hospital, Hershey, Penn., presented findings from a retrospective analysis of NSQIP Pediatric (NSQIP-P), an ongoing collaboration between the ACS and the American Pediatric Surgical Association to improve the care of young patients. The researchers evaluated NSQIP-P data from 2013 and 2014 and focused on unplanned readmission within 30 days, including reasons for readmission based on NSQIP-P readmission categories and ICD-9 readmission codes as categorized by the AHRQ Clinical Classification Software. Multivariate logistic regression was used to evaluate factors associated with unplanned readmission.

Dr. Kulaylat reported results from a cohort of 129,849 patients cared for by 64 NSQIP-P participating hospitals. Among these, the all-cause readmission rate was 4.7%. After excluding patients with planned readmissions, the unplanned readmission rate was found to be 3.9%. From this cohort, 28% required reoperation within 30 days, and the median time from discharge to unplanned readmission was 8 days, with an interquartile range between 3 and 14 days.

Among the procedures captured in NSQIP-P, neurosurgery accounted for the highest readmission rate (10.8%), followed by general/thoracic surgery (5.2%), urology (2.6%), ENT (2%), orthopedic (1.9%), and plastic and reconstructive surgery (1.3%). The most common reason for readmission was surgical site infection at 23%, followed by GI complications such as ileus, obstruction, and constipation (17%); pulmonary-related complications (9%); device-related complications including shunt malfunction (8%); neurologic (7%); pain (6%); other medical diseases (6%); sepsis (5%); electrolytes/dehydration (5%); and urinary tract infection (UTI, 3%). It is estimated that at least two-thirds of unplanned readmissions (63%) were directly related to surgery. “These reasons for readmission and their frequency closely parallel what is seen in adults, with the exception of bleeding complications, which were rare in children compared to adults,” Dr. Kulaylat said.

The top five CPT codes associated with readmissions were laparoscopic appendectomy, laparoscopic gastrostomy tube placement, and three additional codes related to placement and replacement/revision of ventricular shunts/catheters.

Reasons for readmission varied among specialties. For example, among general and thoracic surgery, surgical-site infections (SSI) and GI-related issues dominated, while in neurosurgery SSI and device issues dominated. In urology, UTIs were the most frequent, while ENT had a greater proportion of pulmonary complications. Certain patient variables were also associated with an increased risk of hospital readmission, including comorbidities related to GI, CNS, renal, and immunosuppression and nutrition (P less than .001 for all). The strongest association was the occurrence of a postoperative complication, namely a post-discharge complication.

“The granularity of NSQIP-P can continue to be refined to help predict who is likely to get readmitted or if specific follow-up strategies might identify those headed to readmission,” remarked Robert E. Cilley, MD, a senior author and surgeon-in-chief at Penn State Children’s Hospital. Dr. Kulaylat acknowledged certain limitations of the study, including its retrospective design, the potential for data entry/data interpretation error, and that the researchers were unable to adjust for clustering at the hospital level. Directions of future research include a plan to study readmissions and predictive factors at the procedural level, establish risk-adjusted specialty/procedural-specific benchmarks for readmission rates, and refine the accuracy and reliability of the readmission data. “With these NSQIP-P data there is substantial opportunity for quality improvement as we strive to improve the care of children everywhere,” Dr. Kulaylat said. He reported having no relevant disclosures.

[email protected]

SAN DIEGO – Readmission rates and the underlying reasons for them vary between medical specialties following surgery in children, a study of national data suggests.

“Hospital readmission is a very hot topic, particularly in light of the Affordable Care Act,” Afif N. Kulaylat, MD, said at the American College of Surgeons/National Surgical Quality Improvement Program National Conference. “Beyond economic costs there are very tangible costs to patients that we must consider. Readmissions have been associated with significant morbidity for patients. They often herald or implicate a postoperative complication. There are also indirect costs to patients and families such as time off from school or work.”

Dr. Kulaylat, of the division of pediatric surgery at Penn State Children’s Hospital, Hershey, Penn., presented findings from a retrospective analysis of NSQIP Pediatric (NSQIP-P), an ongoing collaboration between the ACS and the American Pediatric Surgical Association to improve the care of young patients. The researchers evaluated NSQIP-P data from 2013 and 2014 and focused on unplanned readmission within 30 days, including reasons for readmission based on NSQIP-P readmission categories and ICD-9 readmission codes as categorized by the AHRQ Clinical Classification Software. Multivariate logistic regression was used to evaluate factors associated with unplanned readmission.

Dr. Kulaylat reported results from a cohort of 129,849 patients cared for by 64 NSQIP-P participating hospitals. Among these, the all-cause readmission rate was 4.7%. After excluding patients with planned readmissions, the unplanned readmission rate was found to be 3.9%. From this cohort, 28% required reoperation within 30 days, and the median time from discharge to unplanned readmission was 8 days, with an interquartile range between 3 and 14 days.

Among the procedures captured in NSQIP-P, neurosurgery accounted for the highest readmission rate (10.8%), followed by general/thoracic surgery (5.2%), urology (2.6%), ENT (2%), orthopedic (1.9%), and plastic and reconstructive surgery (1.3%). The most common reason for readmission was surgical site infection at 23%, followed by GI complications such as ileus, obstruction, and constipation (17%); pulmonary-related complications (9%); device-related complications including shunt malfunction (8%); neurologic (7%); pain (6%); other medical diseases (6%); sepsis (5%); electrolytes/dehydration (5%); and urinary tract infection (UTI, 3%). It is estimated that at least two-thirds of unplanned readmissions (63%) were directly related to surgery. “These reasons for readmission and their frequency closely parallel what is seen in adults, with the exception of bleeding complications, which were rare in children compared to adults,” Dr. Kulaylat said.

The top five CPT codes associated with readmissions were laparoscopic appendectomy, laparoscopic gastrostomy tube placement, and three additional codes related to placement and replacement/revision of ventricular shunts/catheters.

Reasons for readmission varied among specialties. For example, among general and thoracic surgery, surgical-site infections (SSI) and GI-related issues dominated, while in neurosurgery SSI and device issues dominated. In urology, UTIs were the most frequent, while ENT had a greater proportion of pulmonary complications. Certain patient variables were also associated with an increased risk of hospital readmission, including comorbidities related to GI, CNS, renal, and immunosuppression and nutrition (P less than .001 for all). The strongest association was the occurrence of a postoperative complication, namely a post-discharge complication.

“The granularity of NSQIP-P can continue to be refined to help predict who is likely to get readmitted or if specific follow-up strategies might identify those headed to readmission,” remarked Robert E. Cilley, MD, a senior author and surgeon-in-chief at Penn State Children’s Hospital. Dr. Kulaylat acknowledged certain limitations of the study, including its retrospective design, the potential for data entry/data interpretation error, and that the researchers were unable to adjust for clustering at the hospital level. Directions of future research include a plan to study readmissions and predictive factors at the procedural level, establish risk-adjusted specialty/procedural-specific benchmarks for readmission rates, and refine the accuracy and reliability of the readmission data. “With these NSQIP-P data there is substantial opportunity for quality improvement as we strive to improve the care of children everywhere,” Dr. Kulaylat said. He reported having no relevant disclosures.

[email protected]

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.