SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.

Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”

In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).

The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

By the time this column appears in print we will know whether the US Senate passed a version of the GOP health care bill. If so, millions of our patients will be at risk of losing insurance coverage in the name of tax and deficit reduction. I refer you to an article I wrote for the June issue of Clinical Gastroenterology and Hepatology about the potential transition from Obamacare to Trumpcare.

Our “Flashback” article this month concerns another long-running Congressional issue: repeal of the Sustainable Growth Rate and implementation of value-based reimbursement. We thank Dr. Larry Kosinski for his commentary and for successfully creating the first GI-specific alternative payment model to be endorsed by CMS.

John I. Allen, MD, MBA, AGAF, FACP

Editor in Chief

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this Update we review the results of 4 recent investigations that have important implications:

• the first analysis of the US Zika Virus Infection in Pregnancy Registry
• a study revealing an improved antibiotic regimen to prevent postcesarean infection
• an important new methodology for reducing the rate of perinatal transmission of hepatitis B virus (HBV) infection
• the risks and benefits of combination antiretroviral therapy (ART) in pregnancy.

Zika virus-associated birth defect rates similar regardless of symptom presence; first-trimester exposure has highest rate of anomalies

Honein MA, Dawson AL, Petersen EE, et al; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA. 2017;317(1):59-68.

Honein and colleagues provide a summary of the data from the US Zika Virus in Pregnancy Registry (a collaboration between the Centers for Disease Control and Prevention and state and local health departments), estimating the proportion of fetuses and infants with birth defects based on maternal symptoms of Zika virus infection and  trimester of possible infection.

Related article:
Zika virus: Counseling considerations for this emerging perinatal threat

Details of the study

The authors evaluated the outcomes of 442 women who had laboratory evidence of a possible Zika virus infection during pregnancy. Overall, 26 infants (6%; 95% confidence interval (CI), 4%-8%) had evidence of birth defects related to the Zika virus. Of note, abnormalities were detected in 16 of the 271 children (6%; 95% CI, 4%-9%) born to women who were asymptomatic and 10 of 167 (6%; 95% CI, 3%-11%) children delivered to women with symptomatic infections. 

The most common birth defect was microcephaly, although other serious central nervous system abnormalities were noted as well. Nine of 85 women (11%; 95% CI, 6%-19%) who had exposure only during the first trimester had infants with birth defects. There were no documented abnormalities in infants born to mothers who developed Zika virus infection only in the second or third trimester. 

Related article:
Zika virus update: A rapidly moving target

Key study findings

This article is important for several reasons. First, the authors describe the largest series of pregnant women in the United States with Zika virus infection. All of these patients developed Zika virus infection as a result of foreign travel or exposure to sexual partners who had traveled to Zika virus endemic areas. Second, the authors confirmed findings that previously had been based only on mathematical models rather than on actual case series. Specifically, they demonstrated that the risk of a serious birth defect following first-trimester exposure to Zika virus infection was approximately 11%, with a 95% CI that extended from 6% to 19%. Finally, Honein and colleagues highlighted the key fact that the risk of a serious birth defect was comparable in mothers who had either an asymptomatic or a symptomatic infection, a finding that seems somewhat counterintuitive.

Read about prophylaxis for postcesarean infection

Two antibiotics before cesarean delivery reduce infection rates further than one agent

Tita AT, Szychowski JM, Boggess K, et al; for the C/SOAP Trial Consortium. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016;375(13):1231-1241.

Tita and colleagues reported the results of a multicenter trial that was designed to assess whether a combination of 2 antibiotics, including one that specifically targets ureaplasma species, provided more effective prophylaxis against postcesarean infection than single-agent prophylaxis.

Details of the study

The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial was conducted at 14 centers in the United States and included 2,013 women who were at least at 24 weeks' gestation and who had a cesarean delivery during labor or after membrane rupture.

The authors randomly assigned 1,019 women to receive 500 mg of intravenous azithromycin plus conventional single-agent prophylaxis (usually cefazolin) and 994 women to receive a placebo plus conventional prophylaxis. The primary outcome was the composite of endometritis, wound infection, or other infection occurring within 6 weeks.

The authors observed that the primary outcome occurred in 62 women (6.1%) who received azithromycin plus conventional prophylaxis and in 119 women (12%) who received only single-agent prophylaxis. The relative risk of developing a postoperative infection was 0.51 in women who received the combined therapy. There were significant differences between the 2 groups in both the rates of endometritis (3.8% vs 6.1%, P = .02) and wound infection (2.4% vs 6.6%, P<.001). There were no differences between the groups in the frequency of the secondary neonatal composite outcome, which included neonatal death and serious neonatal complications.

Related article:
Preventing infection after cesarean delivery: 5 more evidence-based measures to consider

Efficacy of dual-agent prophylaxis

At present, the standard of care is to administer prophylactic antibiotics to all women having cesarean delivery, including women having a scheduled cesarean in the absence of labor or ruptured membranes. Multiple studies have shown clearly that prophylaxis reduces the frequency of endometritis and, in high-risk patient populations, wound infection, and that prophylaxis is most beneficial when administered prior to the time the surgical incision is made. The most commonly used drug for prophylaxis is cefazolin, a first-generation cephalosporin. The usual recommended dose is 2 g, administered immediately prior to surgery.^3,4

Although most centers in the United States traditionally have used just a single antibiotic for prophylaxis, selected recent reports indicate that expanding the spectrum of activity of prophylactic antibiotics can result in additional beneficial effects. Specifically, Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection.⁵ They showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis. In a follow-up report from the same institution, Tita and colleagues demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.⁶ Of note, in both these investigations, the antibiotics were administered after cord clamping. In a subsequent report, Ward and Duff showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a combined rate of endometritis and wound infection that was less than 3%.⁷

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

C/SOAP trial confirmed lower infection rates with combined regimen

Results of the present study confirm the findings of these 3 investigations. The trial included a large sample size. The study was carefully designed, and the end points were clearly defined. It included only patients at increased risk for postoperative infection by virtue of being in labor or having ruptured membranes at the time of cesarean delivery. Patients who received standard prophylaxis, usually cefazolin, plus azithromycin had a significantly lower risk of postcesarean endometritis and wound infection compared with patients who received a single antibiotic. The overall risk of infection was reduced by an impressive 50%.  
 

Read about reducing HBV transmission

Tenofovir treatment in pregnant women with HBV reduces vertical transmission

Pan CQ, Duan Z, Dai E, et al; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324-2334.

A multicenter, open-label, randomized, parallel-group investigation was conducted from March 2012 to June 2013 at academic tertiary care centers in 5 geographic regions of China. Two hundred mothers, who were positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and who had HBV DNA concentrations of 200,000 IU/mL or greater, were randomly assigned in a 1:1 ratio to either tenofovir or to usual treatment. Exclusion criteria were coexistent viral infections or medical conditions, renal failure, laboratory abnormalities, fetal deformities, and use of many medications.

Related article:
5 ways to reduce infection risk during pregnancy

Details of the study

Women in the active treatment group received tenofovir 300 mg by mouth daily from 30 to 32 weeks' gestation until postpartum week 4. Patients were monitored every 4 weeks in the antepartum period for adverse events and laboratory abnormalities. In the postpartum period, mother-infant dyads were evaluated at weeks 4, 12, 24, and 28.

Primary outcomes were the rates of mother-to-child transmission and birth defects with, or without, tenofovir exposure. Secondary outcomes were the percentage of mothers who had an HBV DNA serum concentration of less than 200,000 IU/mL at delivery and the percentage of mothers with HBeAg or HBsAg loss or seroconversion at postpartum week 28. Safety outcomes included the adverse event profile of tenofovir in mothers and safety events in the mother-infant dyads. These outcomes encompassed  all adverse events and drug discontinuations in patients who received at least one dose of tenofovir.

Sixty-eight percent of mothers in the tenofovir group, compared with 2% of mothers in the control group, had HBV levels less than 200,000 IU/mL at delivery (P<.001). The rate of mother-to-child HBV transmission at postpartum week 28 was lower in the tenofovir group. In the intention-to-treat analysis, the rate was 5% (95% CI, 1-10; 5 of 97 infants) in the tenofovir group versus 18% (95% CI, 10-26; 18 of 100 infants) in the control group (P = .007). In the per-protocol analysis, the rate was 0% (95% CI, 0-3; 0 of 92 infants) in the tenofovir group versus 7% (95% CI, 2-12; 6 of 88 infants) in the control group (P = .01). Maternal and infant safety profiles were similar between the 2 groups, with the exception of elevated creatinine kinase and alanine aminotransferase levels in mothers treated with tenofovir. Maternal HBV serologic titers did not differ significantly between the 2 groups.

Study strengths and limitations

This study's strengths include a multicenter, randomized controlled design, with strict inclusion and exclusion criteria. The results are clinically relevant and of global impact, with potential to decrease morbidity and  mortality from HBV infection in children born to infected mothers. 

A limitation, however, is that the study was probably underpowered to detect small differences in the rate of birth defects between the tenofovir and usual-care treatment groups. Additionally, some patients ceased taking tenofovir in the postpartum time period. Abrupt cessation may be associated with acute, severe HBV exacerbation.  

Benefits of ART for reducing mother-to-baby HIV transmission outweigh higher risk of adverse outcomes

Fowler MG, Qin M, Fiscus SA, et al; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med. 2016;375(18):1726-1737.

Part of the larger PROMISE (Promoting Maternal and Infant Survival Everywhere) trial, a study by Fowler and colleagues compared the relative efficacy and safety of various proven ART strategies for prevention of mother-to-child transmission of HIV infection in women with relatively high CD4 counts.

Details of the study

The trial was conducted at 14 sites in 7 countries. Patients were stratified according to HBV coinfection status and country of origin. The primary efficacy outcome was frequency of early infant HIV infection.

Women were randomly assigned to 1 of 3 treatment categories:

• zidovudine alone (zidovudine plus a single intrapartum dose of nevirapine, followed by 6 to 14 days of tenofovir plus emtricitabine postpartum)  
• zidovudine-based ART (zidovudine in combination with lamivudine and lopinavir-ritonavir)  
• tenofovir-based ART (tenofovir in combination with emtricitabine and lopinavir-ritonavir). 

All regimens were continued through 6 to 14 days postpartum. All infants received nevirapine at birth and in the immediate postpartum period.

Two trial periods. During period 1 (April 2011-September 2012), safety data on tenofovir in pregnancy were limited. Women without HBV coinfection were assigned only to zidovudine alone or zidovudine-based ART. During period 2 (October 2012-October 2014), since more information about tenofovir use in pregnancy was available, the study protocol was modified to allow women to be assigned to any of the 3 regimens, regardless of their HBV status.

Inclusion criteria were as follows: CD4 count of at least 350 cells/mm3 (or country-specific threshold for initiating triple-drug ART, if that threshold was higher), gestation of at least 14 weeks and not in labor, no previous use of triple-drug ART, no clinical or immune-related indication for triple-drug ART, hemoglobin level of at least 6.5 g/dL, an absolute neutrophil count of at least 750 cells/mm3, an alanine aminotransferase level of less than 2.5 times the upper limit of normal range, an estimated creatinine clearance of greater than 60 mL/min, and no serious pregnancy complications. Patients were excluded if they had active tuberculosis, HBV infection requiring treatment, a structural or conduction heart defect, or a fetus with a serious congenital malformation.

Primary outcomes. The primary efficacy outcome was early infant HIV infection, defined as a positive infant HIV nucleic acid test result at birth or at 1 week postpartum. The primary safety outcome was a composite of adverse events.

Adverse events in mothers were defined as hematologic abnormalities, abnormal blood chemical values, or abnormal signs/symptoms during pregnancy through 1 week postpartum. Severe pregnancy composite outcomes were low birth weight (<2,500 g), preterm delivery before 37 weeks' gestation, spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), or congenital anomaly. Adverse events in infants were defined as death from any cause, hematologic abnormalities or abnormal blood chemical values, and abnormal signs/symptoms through 1 week postpartum.

A total of 3,490 mother-infant sets were included in the analysis (2,261 during trial period 1 and 1,229 during trial period 2). Baseline maternal characteristics were well balanced between groups. Most women were African, young (median age, 26 years), and asymptomatic.

Related article:
2016 Update on infectious disease

Study results

The combined maternal ART-treated groups had significantly lower rates of early transmission of HIV infection compared with the zidovudine-alone group (0.5% vs 1.8%, -1.3 percentage points; CI, -2.1 to -0.4). The zidovudine-based ART-treated group had a significantly higher rate of infant HIV-free survival through postpartum week 1 than did the zidovudine-alone group (P = .001) or the tenofovir-based ART group (P = .002).

When examining trial periods 1 and 2 combined, the zidovudine-based ART group experienced significantly higher rates of any adverse event than those receiving zidovudine alone (21.1% vs 17.3%, P = .008) and higher rates of abnormal blood chemical values (5.8% vs 1.3%, P<.001). During period 2 alone, the tenofovir-based ART group had significantly higher rates of abnormal blood chemical values than did the zidovudine-alone group (2.9% vs 0.8%, P = .03). There were no significant differences between the 2 ART treatment groups. No maternal deaths occurred during the study, and the trial-drug discontinuation rate was low (2%-5%) and did not vary among the 3 groups.

During trial periods 1 and 2, the zidovudine-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (40% vs 27.5%, P<.001). These included low birth weight less than 2,500 g (23% vs 12%) and preterm delivery before 37 weeks (20.5% vs 13.1%). During trial period 2, the tenofovir-based ART group had significantly higher rates of adverse pregnancy outcomes than did the zidovudine-alone group (34.7% vs 27.2%, P = .04). There were no significant differences for any outcome between the 2 ART-treated groups, and there were no significant differences in stillbirth or spontaneous abortion and congenital anomalies among the 3 groups.

Regarding severe pregnancy outcomes, there were no significant differences (composite or individual) between the zidovudine-based ART group and the zidovudine-alone group. The tenofovir-based ART group experienced significantly higher rates of composite severe adverse pregnancy outcomes compared with the zidovudine-based ART group (9.2% vs 4.3%, P = .02), and very preterm birth before 34 weeks (6.0% vs 2.6%, P = .04).

Infant safety outcomes were also examined. There were no significant differences for composite or individual adverse neonatal outcomes other than death. The tenofovir-based ART group experienced a significantly higher rate of infant death than did the zidovudine-based ART group (4.4% vs 0.6%, P<.001). However, a post hoc analysis suggested that extreme prematurity contributed to the infant mortality.

Limitations of the study

This study had minor limitations. It divided patients into only 2 major categories with respect to gestational age--more than or less than 34 weeks. Some maternal medical conditions, such as malaria, were not controlled for. In addition, breastfeeding and formula feeding were combined for analysis, and we know that breastfeeding would inherently confer a higher risk of HIV transmission. 

Nevertheless, this study was thoughtfully designed and carefully conducted, and the results are of significant global impact.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com
 

LAS VEGAS – One of the most intriguing clues that suggest the metabolic syndrome or one of its components might cause hand osteoarthritis comes from a recent study of middle-aged HIV-positive patients, David T. Felson, MD, asserted at the World Congress on Osteoarthritis.

“This is an important study. The identification of an unusual cohort, which otherwise wasn’t supposed to get a particular disease, has really helped us to determine the cause of diseases in other circumstances,” said Dr. Felson, a rheumatologist who is professor of medicine and epidemiology and director of the clinical epidemiology research and training unit at Boston University. He cited an example that also happens to have been related to HIV: Kaposi’s sarcoma in gay men “that alerted us initially to the existence of HIV infection,” he commented.

Other evidence to suggest that metabolic factors are causally related to hand OA comes from animal models, as well as from large population-based cohort studies, including the Netherlands Epidemiology of Obesity (NEO) study. NEO involved 6,673 middle-aged Dutch men and women. Metabolic syndrome was associated with increased rates of both hand OA and knee OA in analyses unadjusted for body weight. However, when the Leiden University investigators adjusted for body weight, the association between metabolic syndrome and knee OA went away, whereas the association between metabolic syndrome and hand OA remained strong (Ann Rheum Dis. 2015 Oct;74[10]:1842-7).

This has uniformly been the case in other cohort studies reporting an association between metabolic syndrome and knee OA: upon adjusting for body mass index (BMI), there is no longer a residual relationship between metabolic syndrome and knee OA.

“One of the challenges in studying metabolic syndrome and knee osteoarthritis is that all the components of the metabolic syndrome are strongly correlated with obesity, and obesity is a major risk factor for knee osteoarthritis through its effects on joint loading. So obesity – at least for knee osteoarthritis – is an enormous confounder,” Dr. Felson said.

The findings from NEO and other large cohort studies underscore a key point: “Metabolic syndrome is not a risk factor for knee osteoarthritis, despite a lot of hullabaloo to the contrary. It doesn’t emerge in cohort studies as an important factor,” according to the rheum

Thinkstock/ LarsNeumann

bjancin@frontlinemedcom.com
 

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

---

Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

---

Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

CASE Patient wants minimally invasive surgery for her fibroids, and no hysterectomy

A 44-year-old G1P1 woman comes to the office to discuss her uterine fibroids, heavy menstrual bleeding, and urinary frequency. Treatment with oral contraceptives has not been effective in reducing the bleeding. She now wants surgical treatment without a hysterectomy (the hysterectomy was recommended by her previous gynecologist). On examination, a 14-week-size irregular uterus is felt. Myomectomy is discussed, and the patient asks if minimally invasive surgery (MIS) is possible. Complete blood cell count testing shows a hemoglobin level of 9.4 g/dL. Pelvic magnetic resonance imaging (MRI) shows a 6-cm type 2 posterior fundal fibroid and a 6-cm type 5 posterior lower-uterine-segment fibroid (FIGURE 1). These 2 fibroids have regular contours, and enhancement is not increased with contrast, consistent with benign fibroids.

Determining that laparoscopic myomectomy is a good option

Fibroids may affect quality of life—they may cause heavy menstrual bleeding, pelvic pain or pressure, or urinary frequency or incontinence. For many women who want large or numerous fibroids removed but the uterus preserved, abdominal myomectomy is required. Smaller and less numerous fibroids usually can be managed laparoscopically or with robotic assistance.

A systematic review of 6 randomized, controlled trials comparing laparoscopic and open myomectomy in 576 patients found that, although laparoscopic myomectomy was associated with longer operative time (approximately 13 minutes), it was also linked to less operative blood loss, fewer overall complications, reduced postoperative pain, and faster recovery.¹ However, wide application of the laparoscopic approach may be limited by the size and number of fibroids that can be reasonably removed and by the surgical skill needed for fibroid excision and laparoscopic suturing.

Four imaging modalities can be used for fibroids: transvaginal sonography (TVS), saline-infusion sonography (SIS), hysteroscopy, and MRI. TVS is the most readily available and least costly modality used to differentiate fibroids from other pelvic pathology; SIS provides contrast for the endometrial cavity and better defines submucous fibroids; and hysteroscopy detects visually apparent distortion of the cavity. MRI, however, provides the most complete evaluation of size, position, and number of fibroids.

A study comparing TVS, SIS, hysteroscopy, and MRI found that number and position of fibroids were best identified with MRI.² In addition, with MRI, the proximity of the fibroids and uterus to the bladder, rectum, and iliac bones can be evaluated. As tactility in laparoscopic and robot-assisted surgery is very limited, surgeons who use MRI to accurately assess fibroids preoperatively may be able to avoid missing them during the procedure.³ MRI also can be used reliably to diagnose adenomyosis and may be able to help identify uterine sarcoma.

Tip. For all women considering laparoscopic or robot-assisted myomectomy, I order pelvic MRI with and without contrast. Having the radiologist limit the number of MRI sequences may reduce the cost and make it comparable to that of other imaging modalities. I request T2-weighted MRI scans in the coronal, sagittal, and axial planes; in addition, to determine distortion of the uterine cavity by submucous fibroids, I request scans in the planes parallel with and perpendicular to the uterine axis. One gadolinium-enhanced T1-weighted MRI scan is needed to evaluate perfusion.

Although radiologists are experts in image interpretation, they are unfamiliar with the treatments and surgical issues that gynecologists must consider. Reading MRI scans for fibroids is straightforward, and gynecologists who regularly treat women with fibroids should consider viewing images with a radiologist until they become proficient.

Related article:
Surgical management of broad ligament fibroids

Surgeons who have the experience and skill and know the size, number, and position of fibroids are able to select the appropriate candidates for laparoscopic myomectomy. Authors of a study of 2,050 laparoscopic myomectomies found that fibroids larger than 5 cm, removal of more than 3 fibroids, and broad ligament fibroids were more likely to be associated with major complications, including visceral injury, conversion to laparotomy, and bleeding requiring blood transfusion.⁴

In laparoscopic myomectomy, uterus reconstruction requires laparoscopic suturing. Although robot-assisted myomectomy may make laparoscopic suturing easier, the added cost, longer operative time, and unimproved outcomes must be considered too.

Read about trocar placement and managing blood loss

Trocar placement

Place the patient in the dorsal lithotomy position.

Tip. For most women, I do not use a uterine manipulator, as my assistant can manipulate the uterus with laparoscopic graspers.

Port placement should be based on the position and size of the fibroids to be removed. Laparoscopic suturing is more ergonomic with 2 ports placed on one side of the patient (FIGURE 2). For suture access, a 12-mm port is placed about 2 cm medial to the iliac crest and a 5-mm port is placed medial to the 12-mm port, near the level of the umbilicus. Lateral trocars should be placed high, above the superior aspect of the uterus, to make it easier to access the fibroids, and lateral to the inferior epigastric vessels, to avoid injuring those vessels. If the uterus is near or above the umbilicus, a left upper quadrant approach may be used, with the access ports placed above the umbilicus.

Related article:
How to avoid major vessel injury during gynecologic laparoscopy

Managing intraoperative blood loss

I use a combination of 3 agents to reduce intraoperative blood loss during laparoscopic myomectomy: preoperative misoprostol and tranexamic acid and intraoperative vasopressin. Although there are no data showing an advantage in using these drugs together, the agents have different mechanisms of action and no negative interactions.

Injected below the vascular pseudocapsule, 20 units of vasopressin in 100 mL of normal saline causes vasoconstriction of capillaries, small arterioles, and venules. Avoid intravascular injection given that bradycardia and cardiovascular collapse have been reported (rare cases). Loss of peripheral pulses, bradycardia, unmeasurable blood pressure, and cardiac complications have been reported after myometrial injection of ≥5 units of vasopressin.⁵

Although vasopressin is a powerful vasoconstrictor, these clinical findings are often interpreted as severe hypotension. However, evaluation of peripheral arterial blood flow by Doppler ultrasonography has revealed severe vasospasm and increased proximal blood pressure.⁵ Keep this potential reaction in mind to avoid misinterpreting findings and treating a patient with vasopressors. Presence of palpable carotid pulses and maintenance of normal partial pressure of end-tidal carbon dioxide can help differentiate peripheral vasospasm from global hypotension.

Use of vasopressin to reduce blood loss during myomectomy is off-label. On occasion, I apply a tourniquet around the lower uterine segment, including the infundibular pelvic ligaments. I use a red Robinson catheter, throw 1 tie in front of the uterus, pull with graspers on both ends until it is tight, and then clamp the half-knot with a locking grasper.

Tip. Although a salvage-type autologous blood transfusion device may be used during laparoscopic or robot-assisted myomectomy, cases in which this device is considered for very large or multiple fibroids might be better managed with abdominal myomectomy.

Read about surgical technique

Surgical technique

After injecting vasopressin, I use a high-frequency mechanical vibration scalpel to incise the myometrium directly over a prominent fibroid and carry the incision deeply until fibroid tissue is definite. Alternatively, a monopolar laparoscopic needle can be used in cut mode—which also limits damage to the myometrium.

Tip. The course of vessels over a fibroid is unpredictable, and we cannot be certain that any uterine incision will avoid bleeding. Therefore, I make transverse incisions, which allow more ergonomic laparoscopic suturing.

It is important to incise completely through the myometrium and through the pink-red pseudocapsule containing the vascular network surrounding the fibroid. This plane is often deeper than usually recognized and can be identified just over the white fibroid.

The fibroid is grasped with a tenaculum for traction, and countertraction is applied with a grasper on the myometrial edges. Once the fibroid is reached, graspers and the mechanical vibration scalpel are used to tease the pseudocapsule away from the fibroid (VIDEO).

Watch the video that accompanies this article:

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Laparoscopic myomectomy technique

 

 

 

Tip. Staying under the pseudocapsule reduces bleeding and may preserve the tissue’s growth factors and neurotransmitters, which are thought to promote wound healing.⁶

Dissection with the mechanical vibration scalpel (or monopolar needle) should be performed under visual control to identify the tissue adhering to the fibroid, which is desiccated and then divided. The fibroid is dissected until free of the myometrium and is placed in the right lower abdomen. Small fibroids can be strung together on a long suture so none will be lost. Using bipolar paddles, desiccate large bleeding vessels in the myometrial defect sparingly, with care taken to avoid devascularizing the myometrium, which might compromise wound healing. Myometrial repair should be performed in accordance with the accepted surgical technique used in laparotomy.

Place delayed absorbable sutures in 2 or 3 layers, as needed, to reapproximate the myometrium and secure hemostasis.

Tip: I use 0 polydioxanone interrupted figure-of-8 sutures, but continuous running sutures with or without barbs also can be used. For the serosa, I use a continuous barbed suture in a baseball stitch, which buries both the raw edges of the serosa and the barbs for smooth closure (FIGURE 3). These closure methods have not been compared to see which provides superior wound healing or subsequent wound strength.

The fibroid can be morcellated with an electromechanical morcellator or a scalpel (hand morcellation). Either instrument can be used in contained or uncontained fashion. I insert an electromechanical morcellator through the right lower quadrant incision and morcellate tissue in the anterior midpelvis. Safety requires careful control of the rotating blade and scrutiny of the bowel, bladder, and major vessels. Our operating room has 4 rules for morcellator use:

1. The blade is activated only under direct visualization.
2. Both the surgeon and the assistant must say “ready” before the blade is activated.
3. The hand holding the morcellator must remain still while tissue is being drawn into the device.
4. Any undue resistance from the tissue is cause to stop the blade. This precaution is taken because there is a tendency to drop the blade in an attempt to overcome the resistance.

Tip: I limit rotational forces and scattering of tissue by “pulsing” the blade on and off when morcellating softer tissue.

Various methods of contained morcellation (morcellation in a containment bag) have been described.⁷ In one method, tissue is placed in a bag, the neck of the bag is brought through an enlarged umbilical incision, and the tissue is cut into small pieces until it is entirely removed. Another method is to use an electromechanical morcellator with a specially designed containment bag inside the abdomen. The bag is introduced through a 12-mm port and unfurled inside the abdomen; the specimen is placed in the bag; the neck of the bag is brought out through the port; the bag is insufflated with carbon dioxide; the laparoscope, a 5-mm grasper, and the morcellator tip are passed into the bag; and morcellation is performed. Early studies of contained morcellation reported longer operating times, leaking bags, and visceral injuries. In 2016, the US Food and Drug Administration (FDA) cleared the PneumoLiner containment system but required that its manufacturer (Advanced Surgical Concepts) warn patients and health care providers that its bag has not been proved to reduce the risk of spreading cancer during morcellation procedures.⁸

During laparoscopic myomectomy, fibroid removal by myometrial dissection disperses tissue fragments, and the unprotected fibroid is usually stored in the abdomen until hemostasis is secured and suturing completed. Limiting the rotational forces that lead to further dispersement and irrigating copiously to remove tissue fragments help eliminate residual tissue.

The pelvis and the abdomen are irrigated with normal saline (approximately 3 L) and suctioned multiple times.

Tip. Alternating between the Trendelenburg and reverse Trendelenburg positions allows fluid to wash tissue down to the pelvis, where it is more easily seen and removed.

Careful inspection for tissue fragments and copious irrigation and suctioning are important in reducing the risk that tissue fragments will remain in the peritoneal cavity and parasitic fibroids will develop. In cases of occult leiomyosarcoma (LMS), this step may be particularly important.

I place a knitted fabric of modified cellulose over the hysterotomy suture lines to reduce the incidence of adhesion formation. Once the procedure is complete, the local anesthetic bupivicaine is injected deep into the incision sites. Injecting anesthetic before making the incisions does not provide better pain relief; injecting after the procedure provides pain relief for 6 hours.⁹

Related article:
Robot-assisted laparoscopic myomectomy

Morcellation and risk of leiomyosarcoma

Given the need to prevent laparoscopic morcellators from inadvertently spreading tissue within the peritoneal cavity of women with occult LMS, the FDA issued a safety communication in 2014 warning against their use in the majority of women who undergo myomectomy or hysterectomy for fibroids.¹⁰ However, Pritts and colleagues estimated the prevalence of LMS in women who had surgery for presumed uterine fibroids at about 1 in 2,000 (0.05%), significantly lower than the FDA’s estimate of 1 in 350.^10,11 In 2015, a large population-based prospective registry study found 2 cases of occult LMS in 8,720 fibroid surgery patients (0.02%).¹²

Related article:
The FDA’s review of the data on open power morcellation was “inadequate, irresponsible” and a “disservice to women”

Since LMS metastasizes through the bloodstream, there is no reliable evidence that morcellation influences survival or that electromechanical morcellation is inferior to vaginal or mini-laparotomy morcellation with a scalpel. According to recent publications, compared with MIS, open abdominal surgery is associated with more morbidity and mortality in women.¹³ Since the FDA advisory was issued, the number of abdominal surgeries has increased, as has the number of related complications.¹³

I use electromechanical morcellation techniques for women who want MIS. All surgical procedures have potential risks, and patients’ and physicians’ understanding of risks forms the foundation of medical decision making. The possibility of occult LMS should be considered by women and their gynecologists, and proper informed consent, noting both the LMS risk and the increased risks of abdominal surgery, should be obtained.

Related article:
Tissue extraction: Can the pendulum change direction?

Risk of uterine rupture after laparoscopic myomectomy

After abdominal myomectomy, uterine rupture during pregnancy or delivery is rare, according to reviews of delivery records of many thousands of women.¹⁴ Operative techniques, instruments, and energy sources used during laparoscopic or robot-assisted myomectomy may differ from those used during laparotomy, and anecdotal communications suggest that uterine rupture may be more common after laparoscopic or robot-assisted myomectomy. A meta-analysis of 56 articles (3,685 pregnancies) published between 1970 and 2013 found 29 cases of uterine rupture after myomectomy, with no statistical difference in rupture risk between laparoscopic and abdominal myomectomy.¹⁵ As most reports are case studies or small case series, the incidence of rupture cannot be reliably calculated.

There is no consensus regarding the factors that may increase the risk of uterine rupture after laparoscopic myomectomy. Three factors are postulated to interfere with myometrial wound healing and increase uterine rupture risk: failure to adequately suture myometrial defects, excessive use of monopolar or bipolar electrosurgery with devascularization of the myometrium, and lack of hemostasis with subsequent hematoma formation.¹⁶ It seems prudent that surgeons should adhere to time-tested techniques for abdominal myomectomy. Even with use of ideal surgical techniques, however, individual wound-healing characteristics may predispose to uterine rupture.

CASE Resolved

After giving proper informed consent, the patient underwent laparoscopic myomectomy and electromechanical morcellation. Her 2 fibroids were removed, with a blood loss of 200 mL, and that afternoon she was discharged from the surgery center with written postoperative instructions and oral pain medication. A telephone call the next day found her comfortable, with no nausea or vomiting, and happy to be fibroid free. Pathologic inspection of the morcellated tissue confirmed that the fibroids were benign. At 2-week follow-up, the patient was no longer taking pain medication and was ready to return to work and normal activity. Her fatigue persisted, though, and she arranged to take time to rest during the day.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

Clinician educators face numerous obstacles to their joint mission of facilitating learning while also ensuring high-quality and patient-centered care. Time constraints, including the institution of house officer duty hour limitations,¹ shorter lengths of stay for hospitalized patients,² and competing career responsibilities, combine to create a dynamic learning environment. Additionally, clinician educators must balance the autonomy of their learners with the safety of their patients. They must teach to multiple learning levels and work collaboratively with multiple disciplines to foster an effective team-based approach to patient care. Yet, many clinician educators have no formal training in pedagogical methods.³ Such challenges necessitate increased attention to the work of excellent clinician educators and their respective teaching approaches.

Many studies of clinical teaching rely primarily on survey data of attributes of good clinical teachers.^3-7 While some studies have incorporated direct observations of teaching^8,9 or interviews with clinician educators or learners,^10,11 few have incorporated multiple perspectives from the current team and from former learners in order to provide a comprehensive picture of team-based learning.¹²

The goal of this study was to gain a thorough understanding, through multiple perspectives, of the techniques and behaviors used by exemplary educators within actual clinical environments. We studied attitudes, behaviors, and approaches of 12 such inpatient clinician educators.

Study Design and Sampling

This was a multisite study using an exploratory qualitative approach to inquiry. This approach was used to study the techniques and behaviors of excellent attendings during inpatient general medicine rounds. A modified snowball sampling approach¹³ was used, meaning individuals known to one member of the research team (SS) were initially contacted and asked to identify clinician educators (also referred to as attendings) for potential inclusion in the study. In an effort to identify attendings from a broad range of medical schools, the “2015 U.S. News and World Report Top Medical Schools: Research” rankings¹⁴ were also reviewed, with priority given to the top 25, as these are widely used to represent the best US hospitals. In an attempt to invite attendings from diverse institutions, additional medical schools not in the top 25 as well as historically black medical schools were also included. Division chiefs and chairs of internal medicine and/or directors of internal medicine residency programs at these schools were contacted and asked for recommendations of attendings, both within and outside their institutions, who they considered to be great inpatient teachers. In addition, key experts who have won teaching awards or were known to be specialists in the field of medical education were asked to nominate one or two other outstanding attendings.

By using this sampling method, 59 potential participants were identified. An internet search was conducted to obtain information about the potential participants and their institutions. Organizational characteristics such as geographic location, hospital size and affiliation, and patient population, as well as individual characteristics such as gender, medical education and training, and educational awards received were considered so that a diversity of organizations and backgrounds was represented. The list was narrowed down to 16 attendings who were contacted via e-mail and asked to participate. Interested participants were asked for a list of their current team members and 6 to 10 former learners to contact for interviews and focus groups. Former learners were included in an effort to better understand lasting effects on learners from their exemplary teaching attendings. A total of 12 attending physicians agreed to participate (Table 1). Literature on field methods has shown that 12 interviews are found to be adequate in accomplishing data saturation.¹⁵ Although 2 attendings were located at the same institution, we decided to include them given that both are recognized as master clinician educators and were each recommended by several individuals from various institutions. Hospitals were located throughout the US and included both university-affiliated hospitals and Veterans Affairs medical centers. Despite efforts to include physicians from historically black colleges and universities, only one attending was identified, and they declined the request to participate.

Data Collection

Observations. The one-day site visits were mainly conducted by two research team members, a physician (SS) and a medical anthropologist (MH), both of whom have extensive experience in qualitative methods. Teams were not uniform but were generally comprised of 1 attending, 1 senior medical resident, 1 to 2 interns, and approximately 2 medical students. Occasionally, a pharmacist, clinical assistant, or other health professional accompanied the team on rounds. Not infrequently, the bedside nurse would explicitly be included in the discussion regarding his or her specific patient. Each site visit began with observing attendings (N = 12) and current learners (N = 57) during rounds. Each research team member recorded their own observations via handwritten field notes, paying particular attention to group interactions, teaching approach, conversations occurring within and peripheral to the team, patient-team interactions, and the physical environment. By standing outside of the medical team circle and remaining silent during rounds, research team members remained unobtrusive to the discussion and process of rounds. Materials the attendings used during their teaching rounds were also documented and collected. Rounds generally lasted 2 to 3 hours. After each site visit, the research team met to compare and combine field notes.

Interviews and Focus Groups. The research team then conducted individual, semi-structured interviews with the attendings, focus groups with their current team (N = 46), and interviews or focus groups with their former learners (N = 26; Supplement 1). Eleven of the current team members observed during rounds were unable to participate in the focus groups due to clinical duties. Because the current learners who participated in the focus groups were also observed during rounds, the research team was able to ask them open-ended questions regarding teaching rounds and their roles as learners within this environment. Former learners who were still at the hospital participated in separate focus groups or interviews. Former learners who were no longer present at the hospital were contacted by telephone and individually interviewed by one research team member (MH). All interviews and focus groups were audio-recorded and transcribed.

This study was determined to be exempt by the University of Michigan Institutional Review Board. All participants were informed that their participation was completely voluntary and that they could terminate their involvement at any time.

Data Analysis

Data were analyzed using a thematic analysis approach.¹⁶ Thematic analysis entails reading through the data to identify patterns (and create codes) that relate to behaviors, experiences, meanings, and activities. Once patterns have been identified, they are grouped according to similarity into themes, which help to further explain the findings.¹⁷

After the first site visit was completed, the research team members that participated (SS and MH) met to develop initial ideas about meanings and possible patterns. All transcripts were read by one team member (MH) and, based on review of the data, codes were developed, defined, and documented in a codebook. This process was repeated after every site visit using the codebook to expand or combine codes and refine definitions as necessary. If a new code was added, the previously coded data were reviewed to apply the new code. NVivo® 10 software (QSR International; Melbourne, Australia) was used to manage the data.

Once all field notes and transcripts were coded (MH), the code reports, which list all data described within a specific code, were run to ensure consistency and identify relationships between codes. Once coding was verified, codes were grouped based on similarities and relationships into salient themes by 3 members of the research team (NH, MH, and SM). Themes, along with their supporting codes, were then further defined to understand how these attendings worked to facilitate excellent teaching in clinical settings.

The coded interview data and field notes were categorized into broad, overlapping themes. Three of these major themes include (1) fostering positive relationships, (2) patient-centered teaching, and (3) collaboration and coaching. Table 2 lists each theme, salient behaviors, examples, and selected quotes that further elucidate its meaning.

Fostering Positive Relationships

Attending physicians took observable steps to develop positive relationships with their team members, which in turn created a safe learning environment. For instance, attendings used learners’ first names, demonstrated interest in their well-being, deployed humor, and generally displayed informal actions—uncrossed arms, “fist bump” when recognizing learners’ success, standing outside the circle of team members and leaning in to listen—during learner interactions. Attendings also made it a priority to get to know individuals on a personal level. As one current learner put it, “He asks about where we are from. He will try to find some kind of connection that he can establish with not only each of the team members but also with each of the patients.”

Additionally, attendings built positive relationships with their learners by responding thoughtfully to their input, even when learners’ evaluations of patients required modification. In turn, learners reported feeling safe to ask questions, admit uncertainty, and respectfully disagree with their attendings. As one attending reflected, “If I can get them into a place where they feel like the learning environment is someplace where they can make a mistake and know that that mistake does not necessarily mean that it’s going to cost them in their evaluation part, then I feel like that’s why it’s important.”

To build rapport and create a safe learning environment, attendings used a number of strategies to position themselves as learners alongside their team members. For instance, attendings indicated that they wanted their ideas questioned because they saw it as an opportunity to learn. Moreover, in conversations with learners, attendings demonstrated humility, admitting when they did not know something. One former learner noted, “There have been times when he has asked [a] question…nobody knows and then he admits that he doesn’t know either. So everybody goes and looks it up…The whole thing turns out to be a fun learning experience.”

Attendings demonstrated respect for their team members’ time by reading about patients before rounds, identifying learning opportunities during rounds, and integrating teaching points into the daily work of patient care. Teaching was not relegated exclusively to the conference room or confined to the traditional “chalk talk” before or after rounds but rather was assimilated into daily workflow. They appeared to be responsive to the needs of individual patients and the team, which allowed attendings to both directly oversee their patients’ care and overcome the challenges of multiple competing demands for time. The importance of this approach was made clear by one current learner who stated “…she does prepare before, especially you know on call days, she does prepare for the new patients before coming in to staff, which is really appreciated… it saves a lot of time on rounds.”

Attendings also included other health professionals in team discussions. Attendings used many of the same relationship-building techniques with these professionals as they did with learners and patients. They consistently asked these professionals to provide insight and direction in patients’ plans of care. A former learner commented, “He always asks the [nurse] what is her impression of the patient...he truly values the [nurse’s] opinion of the patient.” One attending reiterated this approach, stating “I don’t want them to think that anything I have to say is more valuable than our pharmacist or the [nurse].”

Patient-Centered Teaching

Attending physicians modeled numerous teaching techniques that focused learning around the patient. Attendings knew their patients well through review of the medical records, discussion with the patient, and personal examination. This preparation allowed attendings to focus on key teaching points in the context of the patient. One former learner noted, “He tended to bring up a variety of things that really fit well into the clinical scenario. So whether that is talking about what is the differential for a new symptom that just came up for this patient or kind of here is a new paper talking about this condition or maybe some other pearl of physical exam for a patient that has a certain physical condition.”

Attendings served as effective role models by being directly involved in examining and talking with patients as well as demonstrating excellent physical examination and communication techniques. One current learner articulated the importance of learning these skills by observing them done well: “I think he teaches by example and by doing, again, those little things: being attentive to the patients and being very careful during exams…I think those are things that you teach people by doing them, not by saying you need to do this better during the patient encounter.”

Collaboration and Coaching

Attending physicians used varied collaboration and coaching techniques to facilitate learning across the entire care team. During rounds, attendings utilized visual aids to reinforce key concepts and simplify complex topics. They also collaborated by using discussion rather than lecture to engage with team members. For instance, attendings used Socratic questioning, asking questions that lead learners through critical thinking and allow them to solve problems themselves, to guide learners’ decision-making. One former learner reported, “He never gives you the answer, and he always asks your opinion; ‘So what are your thoughts on this?’”

Coaching for success, rather than directing the various team members, was emphasized. Attendings did not wish to be seen as the “leaders” of the team. During rounds, one attending was noted to explain his role in ensuring that the team was building connections with others: “When we have a bad outcome, if it feels like your soul has been ripped out, then you’ve done something right. You’ve made that connection with the patient. My job, as your coach, was to build communication between all of us so we feel vested in each other and our patients.”

Attendings also fostered clinical reasoning skills in their learners by encouraging them to verbalize their thought processes aloud in order to clarify and check for understanding. Attendings also placed emphasis not simply on memorizing content but rather prioritization of the patient’s problems and thinking step by step through individual medical problems. One current learner applauded an attending who could “come up with schematics of how to approach problems rather than feeding us factual information of this paper or this trial.”

Additionally, attendings facilitated learning across the entire care team by differentiating their teaching to meet the needs of multiple learning levels. While the entire team was explicitly included in the learning process, attendings encouraged learners to play various roles, execute tasks, and answer questions depending on their educational level. Attendings positioned learners as leaders of the team by allowing them to talk without interruption and by encouraging them to take ownership of their patients’ care. One former learner stated, “She set expectations…we would be the ones who would be running the team, that you know it would very much be our team and that she is there to advise us and provide supervision but also safety for the patients as well.”

This study reveals the complex ways effective attendings build rapport, create a safe learning environment, utilize patient-centered teaching strategies, and engage in collaboration and coaching with all members of the team. These findings provide a framework of shared themes and their salient behaviors that may influence the success of inpatient general medicine clinician educators (Table 3).

There is a broad and voluminous literature on the subject of outstanding clinical teaching characteristics, much of which has shaped various faculty development curricula for decades. This study sought not to identify novel approaches of inpatient teaching necessarily but rather to closely examine the techniques and behaviors of clinician educators identified as exemplary. The findings affirm and reinforce the numerous, well-documented lists of personal attributes, techniques, and behaviors that resonate with learners, including creating a positive environment, demonstrating enthusiasm and interest in the learner, reading facial expressions, being student-centered, maintaining a high level of clinical knowledge, and utilizing effective communication skills.^18-24 The strengths of this study lie within the nuanced and rich observations and discussions that move beyond learners’ Likert scale evaluations and responses.^3-7,12 Input was sought from multiple perspectives on the care team, which provided detail from key stakeholders. Out of these comprehensive data arose several conclusions that extend the research literature on medical education.

In their seminal review, Sutkin et al.¹⁸ demonstrate that two thirds of characteristics of outstanding clinical teachers are “noncognitive” and that, “Perhaps what makes a clinical educator truly great depends less on the acquisition of cognitive skills such as medical knowledge and formulating learning objectives, and more on inherent, relationship-based, noncognitive attributes. Whereas cognitive abilities generally involve skills that may be taught and learned, albeit with difficulty, noncognitive abilities represent personal attributes, such as relationship skills, personality types, and emotional states, which are more difficult to develop and teach.”¹⁸ Our study, thus, adds to the literature by (1) highlighting examples of techniques and behaviors that encompass the crucial “noncognitive” arena and (2) informing best practices in teaching clinical medicine, especially those that resonate with learners, for future faculty development.

The findings highlight the role that relationships play in the teaching and learning of team-based medicine. Building rapport and sustaining successful relationships are cornerstones of effective teaching.¹⁸ For the attendings in this study, this manifested in observable, tangible behaviors such as greeting others by name, joking, using physical touch, and actively involving all team members, regardless of role or level of education. Previous literature has highlighted the importance of showing interest in learners.^7,19,25-27 This study provides multiple and varied examples of ways in which interest might be displayed.

For patients, the critical role of relationships was evidenced through rapport building and attention to patients as people outside their acute hospitalization. For instance, attendings regularly put patients’ medical issues into context and anticipated future outpatient challenges. To the authors’ knowledge, previous scholarship has not significantly emphasized this form of contextualized medicine, which involves the mindful consideration of the ongoing needs patients may experience upon transitions of care.

Several participants highlighted humility as an important characteristic of effective clinician educators. Attendings recognized that the field produces more new knowledge than can possibly be assimilated and that uncertainty is a mainstay of modern medical care. Attendings frequently utilized self-deprecation to acknowledge doubt, a technique that created a collaborative environment in which learners also felt safe to ask questions. These findings support the viewpoints by Reilly and Beckman that humility and an appreciation for questions and push-back from learners encourage lifelong learning through role modeling.^19,23 In responding to the interviewer’s question “And what happens when [the attending] is wrong?” one learner simply stated, “He makes fun of himself.”

This study has several limitations. First, it was conducted in a limited number of US based healthcare systems. The majority of institutions represented were larger, research intensive hospitals. While these hospitals were purposefully selected to provide a range in geography, size, type, and access to resources, the findings may differ in other settings. Second, it was conducted with a limited number of attendings and learners, which may limit the study’s generalizability. However, enough interviews were conducted to reach data saturation.¹⁵ Because evidence for a causal relationship between quality teaching and student and patient outcomes is lacking,¹⁸ we must rely on imperfect proxies for teaching excellence, including awards and recognition. This study attempted to identify exemplary educators through various means, but it is recognized that bias is likely. Third, because attendings provided lists of former learners, selection and recall biases may have been introduced, as attendings may have more readily identified former learners with whom they formed strong relationships. Fourth, focus was placed exclusively on teaching and learning within general medicine rounds. This was because there would be ample opportunity for teaching on this service, the structure of the teams and the types of patients would be comparable across sites, and the principal investigator was also a general medicine attending and would have a frame of reference for these types of rounds. Due to this narrow focus, the findings may not be generalizable to other subspecialties. Fifth, attendings were selected through a nonexhaustive method. However, the multisite design, the modified snowball sampling, and the inclusion of several types of institutions in the final participant pool introduced diversity to the final list. Finally, although we cannot discount the potential role of a Hawthorne effect on our data collection, the research team did attempt to mitigate this by standing apart from the care teams and remaining unobtrusive during observations.

Using a combination of interviews, focus group discussions, and direct observation, we identified consistent techniques and behaviors of excellent teaching attendings during inpatient general medicine rounds. We hope that all levels of clinician educators may use them to elevate their own teaching.

Disclosure

Dr. Saint is on a medical advisory board of Doximity, a new social networking site for physicians, and receives an honorarium. He is also on the scientific advisory board of Jvion, a healthcare technology company. Drs. Houchens, Harrod, Moody, and Ms. Fowler have no conflicts of interest.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

The role of lymphadenectomy for endometrial cancer has evolved considerably over the last 30 years. While pathologic assessment of the nodes provides important information to tailor adjuvant therapy, 2 randomized trials both reported no survival benefit in women who underwent lymphadenectomy compared with hysterectomy alone.^1,2 Further, these trials revealed that lymphadenectomy was associated with significant short- and long-term sequelae.

SLN biopsy, a procedure in which a small number of nodes that represent the first drainage basins of a primary tumor are removed, has been proposed as an alternative to traditional lymphadenectomy. Although SLN biopsy is commonly used for other solid tumors, few large, multicenter studies have been conducted to evaluate the technique’s safety in endometrial cancer.

Related article:
2016 Update on cancer

Details of the study

The Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial was a prospective trial evaluating the performance characteristics of SLN biopsy in women with clinical stage 1 endometrial cancer at 10 sites in the United States. After cervical injection of indocyanine green, patients underwent robot-assisted hysterectomy with SLN biopsy followed by pelvic lymphadenectomy. Para-aortic lymphadenectomy was performed at the discretion of the attending surgeon. The study’s primary end point was sensitivity of SLN biopsy for detecting metastatic disease in women who had mapping.

Over approximately 3 years, 385 patients were enrolled. Overall, 86% of patients had mapping of at least 1 SLN and 52% had bilateral mapping. Positive nodes were found in 12% of the study population. Among women who had SLNs identified, 35 of 36 nodal metastases were identified (97% sensitivity). Negative SLNs correctly predicted the absence of metastases (negative predictive value) in 99.6% of patients.

Overall, the procedure was well tolerated. Adverse events were noted in 9% of patients, and approximately two-thirds were considered serious adverse events. The most common adverse events were neurologic complications, respiratory distress, nausea and vomiting, and bowel injury in 3 patients. One ureteral injury occurred during SLN biopsy.

Related article:
Does laparoscopic versus open abdominal surgery for stage I endometrial cancer affect oncologic outcomes?

Study strengths and weaknesses

The FIRES study provides strong evidence for the effectiveness of SLN biopsy in women with apparent early stage endometrial cancer. The procedure not only was highly accurate in identifying nodal disease but it also had acceptable adverse events. Further, many of the benefits of SLN biopsy, such as a reduction in lymphedema, will require long-term follow-up.

Consider study results in context. As oncologists consider the role of SLN biopsy in practice, this work should be interpreted in the context of the study design. The study was performed by only 18 surgeons at 10 centers. Prior to study initiation, each site and surgeon underwent formal training and observation to ensure that the technique for SLN biopsy was adequate. Clearly, there will be a learning curve for SLN biopsy, and this study’s results may not immediately be generalizable.

Despite rigorous quality control procedures, there was no nodal mapping in 48% of the hemi-pelvises. In practice, these patients require lymph node dissection. The authors estimated that 50% of patients would still require lymphadenectomy (40% unilateral, 10% bilateral) if SLN mapping was used in routine practice. In addition, while the FIRES trial included women with high-risk histologies, the majority of patients had low-risk, endometrioid tumors. Further study will help to define performance of SLN biopsy in populations at higher risk for nodal metastases.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶

See related editorial

Results of laboratory testing included a positive reactive syphilis immunoglobulin G (IgG) enzyme immunoassay and a positive rapid plasma reagin (RPR) test (titer 1:256). Human immunodeficiency virus (HIV) testing was negative, and serologic testing demonstrated prior immunization to hepatitis B virus. Given the clinical presentation and laboratory findings, secondary syphilis was considered the most probable diagnosis.

The patient was treated with benzathine penicillin G 2.4 million units intramuscularly.

SYPHILIS: A REEMERGING CONDITION

Epidemiology

The rate of reported primary and secondary syphilis cases in the United States has risen since 2001.¹ Most cases occur in men who have sex with men.¹ Additional risk factors include condomless intercourse and drug use.²

Signs and symptoms of the 3 stages

Primary syphilis begins 2 to 3 weeks after inoculation of a mucosal surface.³ This stage is marked by one or more painless chancres and, in some cases, local nontender lymphadenopathy.^3,4 Secondary syphilis presents 4 to 8 weeks later with systemic symptoms including rash, classically involving the palms or soles, lymphadenopathy, myalgia, fever, and weight loss.^2,3 Untreated primary and secondary syphilis may progress to latent or asymptomatic disease.⁵

Tertiary syphilis, defined by the US Centers for Disease Control and Prevention (CDC) as gummas or cardiovascular syphilis, occurs 15 to 30 years after an untreated exposure.^4,6 Neurosyphilis can present at any stage of the disease.⁶

Diagnosis

The diagnosis of syphilis involves a nontreponemal test such as RPR or Venereal Disease Research Laboratory (VDRL) to screen for disease, followed by a treponemal antibody test such as fluorescent treponemal antibody-absorption, Treponema pallidum particle agglutination assay, or syphilis IgG to confirm the diagnosis.⁵ There is no screening test for tertiary disease in patients previously diagnosed with primary or secondary syphilis, but a cerebrospinal fluid (CSF) examination is recommended if neurologic or ocular manifestations are present.⁶

Treatment

Treatment of primary, secondary, and early latent syphilis is a single dose of 2.4 million units of benzathine penicillin G given intramuscularly.⁷ The treatment of late latent and tertiary syphilis is less well defined by the current literature but generally includes penicillin.⁷

Patients with primary and secondary syphilis undergo serologic and clinical evaluation at 6 and 12 months to be assessed for treatment failure or reinfection.⁶ Patients with latent disease require serologic follow-up at 6, 12, and 24 months.⁶ Additionally, CSF analysis should be done if baseline high titers do not fall within 12 to 24 months of treatment or if symptoms suggest syphilis.⁶ Patients with neurosyphilis often require CSF evaluation every 6 months.⁶ Follow-up for patients with tertiary syphilis is less well defined.

Patients coinfected with HIV have special needs and considerations, as outlined in the CDC’s 2015 Sexually Transmitted Diseases Treatment Guidelines.⁶

Sexual contacts of patients with syphilis deserve evaluation. Exposure within 90 days of a patient’s diagnosis with primary, secondary, or latent disease requires treatment regardless of the results of serologic testing.⁶ Persons exposed more than 90 days before diagnosis may undergo serologic testing; however, if results are not immediately available or follow-up is unlikely, the individual should be treated for early syphilis.⁶ If serologic testing results are negative, no treatment is required.⁶