Anne Mounsey, MD

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PRACTICE CHANGER
Consider using nonsterile gloves during minor skin excisions (even those requiring sutures), because the infection rate is not increased compared to using sterile gloves.¹

STRENGTH OF RECOMMENDATION
B: Based on a randomized controlled trial (RCT) conducted in a primary care practice.¹

ILLUSTRATIVE CASE
A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean nonsterile box in the exam room?

Nonsterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that nonsterile gloves do not increase the risk for infection during several types of minor skin procedures.

A partially blinded RCT in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) and nonsterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using nonsterile (0.49%) versus sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile versus nonsterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the CDC and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of nonmelanoma skin cancer, due out this winter, which may provide additional guidance.⁸ A 2003 review instructed primary care providers to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile versus nonsterile glove use for minor skin excisions in a primary care outpatient practice.

Continue for study summary >>

STUDY SUMMARY 
Nonsterile is not inferior
Heal et al¹ conducted a prospective, noninferiority RCT to compare the incidence of infection after minor skin surgery performed by six physicians from a single general practice in Australia using sterile versus nonsterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge; pain or tenderness; localized swelling, redness, or heat at the site; or a diagnosis of skin or soft-tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or nonsterile glove group, and a stitch abscess was not counted as an infection.

The patients’ mean age was 65, and 59% were men. At baseline, there were no large differences between patients in the sterile and nonsterile glove groups in terms of smoking status, anticoagulant or corticosteroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis; skin cancer and precursor; or other.

The incidence of infection in the nonsterile gloves group was 21/241 (8.7%) versus 22/237 in the control group (9.3%). The confidence interval (CI; 95%) for the difference in infection rate (–0.6%) was –4.0% to 2.9%—significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

Continue for what's new >>

WHAT’S NEW 
New evidence questions the need for sterile gloves for in-office excisions
Heal et al¹ demonstrated that in a primary care setting, nonsterile gloves are not inferior to sterile gloves for excisional procedures that require sutures. While standard practice has many family practice providers using sterile gloves for these procedures, this study promotes changing this ­behavior.

Continue for caveats >>

CAVEATS 
High infection rate, other factors may limit generalizability
The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why nonsterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and clinicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the nonsterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves; outcomes were similar in terms of the difference in infection rate between sterile and nonsterile gloves.⁴

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION 
Ingrained habits can be hard to change
Tradition and training die hard. While multiple studies in several settings have found nonsterile gloves to be noninferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway clinicians from ingrained habits.

REFERENCES 
1. Heal C, Sriharan S, Buttner PG, et al. Comparing non-sterile to sterile gloves for minor surgery: a prospective randomized controlled non-inferiority trial. Med J Aust. 2015;202:27-31.
2. Perelman VS, Francis GJ, Rutledge T, et al. Sterile versus nonsterile gloves for repair of uncomplicated lacerations in the emergency department: a randomized controlled trial. Ann Emerg Med. 2004;43:362-370.
3. Mehta D, Chambers N, Adams B, et al. Comparison of the prevalence of surgical site infection with use of sterile versus nonsterile gloves for resection and reconstruction during Mohs surgery. Dermatol Surg. 2014;40: 234-239.
4. Xia Y, Cho S, Greenway HT, et al. Infection rates of wound repairs during Mohs micrographic surgery using sterile versus nonsterile gloves: a prospective randomized pilot study. Dermatol Surg. 2011;37:651-656.
5. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27:97-132.
6. National Institute for Health and Care Excellence. Surgical site infection: prevention and treatment of surgical site infection. www.nice.org.uk/guidance/cg74/chapter/1-recommendations. Accessed November 17, 2015.
7. National Health and Medical Research Council. Australian Guidelines for the Prevention and Control of Infection in Healthcare (2010). www.nhmrc.gov.au/book/html-australian-guideline-sprevention-and-control-infection-healthcare-2010. Accessed November 17, 2015.
8. American Academy of Dermatology. Clinical guidelines. www.aad.org/education/clinical-guidelines. Accessed November 17, 2015.
9. Zuber TJ. Fusiform excision. Am Fam Physician. 2003;67:1539-1544.
10. Heal C, Buettner P, Browning S. Risk factors for wound infection after minor surgery in general practice. Med J Aust. 2006;18:255-258.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(11):723-724, 727. 

PRACTICE CHANGER
Consider using nonsterile gloves during minor skin excisions (even those requiring sutures), because the infection rate is not increased compared to using sterile gloves.¹

STRENGTH OF RECOMMENDATION
B: Based on a randomized controlled trial (RCT) conducted in a primary care practice.¹

ILLUSTRATIVE CASE
A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean nonsterile box in the exam room?

Nonsterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that nonsterile gloves do not increase the risk for infection during several types of minor skin procedures.

A partially blinded RCT in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) and nonsterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using nonsterile (0.49%) versus sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile versus nonsterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the CDC and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of nonmelanoma skin cancer, due out this winter, which may provide additional guidance.⁸ A 2003 review instructed primary care providers to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile versus nonsterile glove use for minor skin excisions in a primary care outpatient practice.

Continue for study summary >>

STUDY SUMMARY 
Nonsterile is not inferior
Heal et al¹ conducted a prospective, noninferiority RCT to compare the incidence of infection after minor skin surgery performed by six physicians from a single general practice in Australia using sterile versus nonsterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge; pain or tenderness; localized swelling, redness, or heat at the site; or a diagnosis of skin or soft-tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or nonsterile glove group, and a stitch abscess was not counted as an infection.

The patients’ mean age was 65, and 59% were men. At baseline, there were no large differences between patients in the sterile and nonsterile glove groups in terms of smoking status, anticoagulant or corticosteroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis; skin cancer and precursor; or other.

The incidence of infection in the nonsterile gloves group was 21/241 (8.7%) versus 22/237 in the control group (9.3%). The confidence interval (CI; 95%) for the difference in infection rate (–0.6%) was –4.0% to 2.9%—significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

Continue for what's new >>

WHAT’S NEW 
New evidence questions the need for sterile gloves for in-office excisions
Heal et al¹ demonstrated that in a primary care setting, nonsterile gloves are not inferior to sterile gloves for excisional procedures that require sutures. While standard practice has many family practice providers using sterile gloves for these procedures, this study promotes changing this ­behavior.

Continue for caveats >>

CAVEATS 
High infection rate, other factors may limit generalizability
The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why nonsterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and clinicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the nonsterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves; outcomes were similar in terms of the difference in infection rate between sterile and nonsterile gloves.⁴

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION 
Ingrained habits can be hard to change
Tradition and training die hard. While multiple studies in several settings have found nonsterile gloves to be noninferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway clinicians from ingrained habits.

REFERENCES 
1. Heal C, Sriharan S, Buttner PG, et al. Comparing non-sterile to sterile gloves for minor surgery: a prospective randomized controlled non-inferiority trial. Med J Aust. 2015;202:27-31.
2. Perelman VS, Francis GJ, Rutledge T, et al. Sterile versus nonsterile gloves for repair of uncomplicated lacerations in the emergency department: a randomized controlled trial. Ann Emerg Med. 2004;43:362-370.
3. Mehta D, Chambers N, Adams B, et al. Comparison of the prevalence of surgical site infection with use of sterile versus nonsterile gloves for resection and reconstruction during Mohs surgery. Dermatol Surg. 2014;40: 234-239.
4. Xia Y, Cho S, Greenway HT, et al. Infection rates of wound repairs during Mohs micrographic surgery using sterile versus nonsterile gloves: a prospective randomized pilot study. Dermatol Surg. 2011;37:651-656.
5. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27:97-132.
6. National Institute for Health and Care Excellence. Surgical site infection: prevention and treatment of surgical site infection. www.nice.org.uk/guidance/cg74/chapter/1-recommendations. Accessed November 17, 2015.
7. National Health and Medical Research Council. Australian Guidelines for the Prevention and Control of Infection in Healthcare (2010). www.nhmrc.gov.au/book/html-australian-guideline-sprevention-and-control-infection-healthcare-2010. Accessed November 17, 2015.
8. American Academy of Dermatology. Clinical guidelines. www.aad.org/education/clinical-guidelines. Accessed November 17, 2015.
9. Zuber TJ. Fusiform excision. Am Fam Physician. 2003;67:1539-1544.
10. Heal C, Buettner P, Browning S. Risk factors for wound infection after minor surgery in general practice. Med J Aust. 2006;18:255-258.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(11):723-724, 727. 

PRACTICE CHANGER
Consider using nonsterile gloves during minor skin excisions (even those requiring sutures), because the infection rate is not increased compared to using sterile gloves.¹

STRENGTH OF RECOMMENDATION
B: Based on a randomized controlled trial (RCT) conducted in a primary care practice.¹

ILLUSTRATIVE CASE
A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean nonsterile box in the exam room?

Nonsterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that nonsterile gloves do not increase the risk for infection during several types of minor skin procedures.

A partially blinded RCT in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) and nonsterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using nonsterile (0.49%) versus sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile versus nonsterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the CDC and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of nonmelanoma skin cancer, due out this winter, which may provide additional guidance.⁸ A 2003 review instructed primary care providers to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile versus nonsterile glove use for minor skin excisions in a primary care outpatient practice.

Continue for study summary >>

STUDY SUMMARY 
Nonsterile is not inferior
Heal et al¹ conducted a prospective, noninferiority RCT to compare the incidence of infection after minor skin surgery performed by six physicians from a single general practice in Australia using sterile versus nonsterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge; pain or tenderness; localized swelling, redness, or heat at the site; or a diagnosis of skin or soft-tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or nonsterile glove group, and a stitch abscess was not counted as an infection.

The patients’ mean age was 65, and 59% were men. At baseline, there were no large differences between patients in the sterile and nonsterile glove groups in terms of smoking status, anticoagulant or corticosteroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis; skin cancer and precursor; or other.

The incidence of infection in the nonsterile gloves group was 21/241 (8.7%) versus 22/237 in the control group (9.3%). The confidence interval (CI; 95%) for the difference in infection rate (–0.6%) was –4.0% to 2.9%—significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

Continue for what's new >>

WHAT’S NEW 
New evidence questions the need for sterile gloves for in-office excisions
Heal et al¹ demonstrated that in a primary care setting, nonsterile gloves are not inferior to sterile gloves for excisional procedures that require sutures. While standard practice has many family practice providers using sterile gloves for these procedures, this study promotes changing this ­behavior.

Continue for caveats >>

CAVEATS 
High infection rate, other factors may limit generalizability
The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why nonsterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and clinicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the nonsterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves; outcomes were similar in terms of the difference in infection rate between sterile and nonsterile gloves.⁴

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION 
Ingrained habits can be hard to change
Tradition and training die hard. While multiple studies in several settings have found nonsterile gloves to be noninferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway clinicians from ingrained habits.

REFERENCES 
1. Heal C, Sriharan S, Buttner PG, et al. Comparing non-sterile to sterile gloves for minor surgery: a prospective randomized controlled non-inferiority trial. Med J Aust. 2015;202:27-31.
2. Perelman VS, Francis GJ, Rutledge T, et al. Sterile versus nonsterile gloves for repair of uncomplicated lacerations in the emergency department: a randomized controlled trial. Ann Emerg Med. 2004;43:362-370.
3. Mehta D, Chambers N, Adams B, et al. Comparison of the prevalence of surgical site infection with use of sterile versus nonsterile gloves for resection and reconstruction during Mohs surgery. Dermatol Surg. 2014;40: 234-239.
4. Xia Y, Cho S, Greenway HT, et al. Infection rates of wound repairs during Mohs micrographic surgery using sterile versus nonsterile gloves: a prospective randomized pilot study. Dermatol Surg. 2011;37:651-656.
5. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27:97-132.
6. National Institute for Health and Care Excellence. Surgical site infection: prevention and treatment of surgical site infection. www.nice.org.uk/guidance/cg74/chapter/1-recommendations. Accessed November 17, 2015.
7. National Health and Medical Research Council. Australian Guidelines for the Prevention and Control of Infection in Healthcare (2010). www.nhmrc.gov.au/book/html-australian-guideline-sprevention-and-control-infection-healthcare-2010. Accessed November 17, 2015.
8. American Academy of Dermatology. Clinical guidelines. www.aad.org/education/clinical-guidelines. Accessed November 17, 2015.
9. Zuber TJ. Fusiform excision. Am Fam Physician. 2003;67:1539-1544.
10. Heal C, Buettner P, Browning S. Risk factors for wound infection after minor surgery in general practice. Med J Aust. 2006;18:255-258.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(11):723-724, 727. 

Illustrative case

A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean non-sterile box in the exam room?

Non-sterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that non-sterile gloves do not increase the risk of infection during several types of minor skin procedures.

A partially blinded, randomized controlled trial (RCT) in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) vs non-sterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using non-sterile (0.49%) vs sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile vs non-sterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the Centers for Disease Control and Prevention (CDC) and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of non-melanoma skin cancer that’s due out this winter, and this may provide additional guidance.⁸ A 2003 review instructed primary care physicians to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile vs non-sterile glove use for minor skin excisions in a primary care outpatient practice.

STUDY SUMMARY: Non-sterile gloves are not inferior to sterile gloves

Heal et al¹ conducted a prospective, randomized, controlled, noninferiority trial to compare the incidence of infection after minor skin surgery performed by 6 physicians from a single general practice in Australia using sterile vs non-sterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge, pain or tenderness, localized swelling or redness or heat at the site, or a diagnosis of skin or soft tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or non-sterile glove group, and a stitch abscess was not counted as an infection.

Tradition and training die hard. A single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

The patients’ mean age was 65 years and 59% were men. At baseline, there were no large differences between patients in the sterile and non-sterile glove groups in terms of smoking status, anticoagulant or steroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis, skin cancer and precursor, or other.

The incidence of infection in the non-sterile gloves group was 21/241 (8.7%; 95% confidence interval [CI], 4.9%-12.6%) vs 22/237 in the control group (9.3%; 95% CI, 7.4%-11.1%). The CI (95%) for the difference in infection rate (-0.6%) was -4.0% to 2.9%. This was significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

WHAT'S NEW: New evidence questions the need for sterile gloves for in-office excisions

Heal et al¹ demonstrated that in a primary care setting, non-sterile gloves are not inferior to sterile gloves for performing excisional procedures that require sutures. While standard practice has many family physicians using sterile gloves for these procedures, this study promotes changing this behavior.

CAVEATS: A high infection rate, other factors might limit generalizability 

The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why non-sterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and physicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the non-sterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves, and had similar outcomes in terms of the difference in infection rate between sterile and non-sterile gloves.⁴

CHALLENGES TO IMPLEMENTATION:  Ingrained habits can be hard to change

Tradition and training die hard. While multiple studies in several settings have found non-sterile gloves are non-inferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean non-sterile box in the exam room?

Non-sterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that non-sterile gloves do not increase the risk of infection during several types of minor skin procedures.

A partially blinded, randomized controlled trial (RCT) in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) vs non-sterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using non-sterile (0.49%) vs sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile vs non-sterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the Centers for Disease Control and Prevention (CDC) and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of non-melanoma skin cancer that’s due out this winter, and this may provide additional guidance.⁸ A 2003 review instructed primary care physicians to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile vs non-sterile glove use for minor skin excisions in a primary care outpatient practice.

STUDY SUMMARY: Non-sterile gloves are not inferior to sterile gloves

Heal et al¹ conducted a prospective, randomized, controlled, noninferiority trial to compare the incidence of infection after minor skin surgery performed by 6 physicians from a single general practice in Australia using sterile vs non-sterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge, pain or tenderness, localized swelling or redness or heat at the site, or a diagnosis of skin or soft tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or non-sterile glove group, and a stitch abscess was not counted as an infection.

Tradition and training die hard. A single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

The patients’ mean age was 65 years and 59% were men. At baseline, there were no large differences between patients in the sterile and non-sterile glove groups in terms of smoking status, anticoagulant or steroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis, skin cancer and precursor, or other.

The incidence of infection in the non-sterile gloves group was 21/241 (8.7%; 95% confidence interval [CI], 4.9%-12.6%) vs 22/237 in the control group (9.3%; 95% CI, 7.4%-11.1%). The CI (95%) for the difference in infection rate (-0.6%) was -4.0% to 2.9%. This was significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

WHAT'S NEW: New evidence questions the need for sterile gloves for in-office excisions

Heal et al¹ demonstrated that in a primary care setting, non-sterile gloves are not inferior to sterile gloves for performing excisional procedures that require sutures. While standard practice has many family physicians using sterile gloves for these procedures, this study promotes changing this behavior.

CAVEATS: A high infection rate, other factors might limit generalizability 

The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why non-sterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and physicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the non-sterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves, and had similar outcomes in terms of the difference in infection rate between sterile and non-sterile gloves.⁴

CHALLENGES TO IMPLEMENTATION:  Ingrained habits can be hard to change

Tradition and training die hard. While multiple studies in several settings have found non-sterile gloves are non-inferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 50-year-old man comes to your office to have a mole removed from his arm. You decide to excise the lesion in your office today. Do you need to use sterile gloves for this procedure, or can you use gloves from the clean non-sterile box in the exam room?

Non-sterile gloves are readily available during a typical office visit and cost up to a dollar less per pair than sterile gloves.^1-3 Studies conducted in settings other than primary care offices have shown that non-sterile gloves do not increase the risk of infection during several types of minor skin procedures.

A partially blinded, randomized controlled trial (RCT) in an emergency department found no significant difference in infection rates between the use of sterile (6.1%) vs non-sterile (4.4%) gloves during laceration repairs.² Similarly, a small RCT in an outpatient dermatology clinic and a larger prospective trial by a Mohs dermatologist showed that infection rates were not increased after Mohs surgery using non-sterile (0.49%) vs sterile (0.50%) gloves.^3,4

Guidelines on the use of sterile vs non-sterile gloves for minor skin excisions in outpatient primary care are difficult to come by. Current guidelines from the Centers for Disease Control and Prevention (CDC) and other agencies regarding surgical site infections are broad and focus on the operating room environment.^5-7

The American Academy of Dermatology is working on a guideline for treatment of non-melanoma skin cancer that’s due out this winter, and this may provide additional guidance.⁸ A 2003 review instructed primary care physicians to use sterile gloves for excisional skin biopsies that require sutures.⁹

The 2015 study by Heal et al¹ appears to be the first RCT to address the question of sterile vs non-sterile glove use for minor skin excisions in a primary care outpatient practice.

STUDY SUMMARY: Non-sterile gloves are not inferior to sterile gloves

Heal et al¹ conducted a prospective, randomized, controlled, noninferiority trial to compare the incidence of infection after minor skin surgery performed by 6 physicians from a single general practice in Australia using sterile vs non-sterile clean gloves. They evaluated 576 consecutive patients who presented for skin excision between June 2012 and March 2013. Eighty-three patients were excluded because they had a latex allergy, were using oral antibiotics or immunosuppressive drugs, or required a skin flap procedure or excision of a sebaceous cyst. The physicians followed a standard process for performing the procedures and did not use topical antibiotics or antiseptic cleansing after the procedure.

The primary outcome was surgical site infection within 30 days of the excision, defined as purulent discharge, pain or tenderness, localized swelling or redness or heat at the site, or a diagnosis of skin or soft tissue infection by a general practitioner. The clinicians who assessed for infection were blinded to the patient’s assignment to the sterile or non-sterile glove group, and a stitch abscess was not counted as an infection.

Tradition and training die hard. A single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

The patients’ mean age was 65 years and 59% were men. At baseline, there were no large differences between patients in the sterile and non-sterile glove groups in terms of smoking status, anticoagulant or steroid use, diabetes, excision site, size of excision, and median days until removal of sutures. The lesions were identified histologically as nevus or seborrheic keratosis, skin cancer and precursor, or other.

The incidence of infection in the non-sterile gloves group was 21/241 (8.7%; 95% confidence interval [CI], 4.9%-12.6%) vs 22/237 in the control group (9.3%; 95% CI, 7.4%-11.1%). The CI (95%) for the difference in infection rate (-0.6%) was -4.0% to 2.9%. This was significantly below the predetermined noninferiority margin of 7%. In a sensitivity analysis of patients lost to follow-up (15 patients, 3%) that assumed all of these patients were without infection, or with infection, the CI was still below the noninferiority margin of 7%. The per-protocol analysis showed similar results.

WHAT'S NEW: New evidence questions the need for sterile gloves for in-office excisions

Heal et al¹ demonstrated that in a primary care setting, non-sterile gloves are not inferior to sterile gloves for performing excisional procedures that require sutures. While standard practice has many family physicians using sterile gloves for these procedures, this study promotes changing this behavior.

CAVEATS: A high infection rate, other factors might limit generalizability 

The overall rate of infection in this study (9%) was higher than that found in the studies from emergency medicine and dermatology literature cited earlier.^2-4 A similarly high infection rate has been found in other studies of minor surgery by Heal et al, including a 2006 study that showed a wound infection rate of 8.6%.¹⁰ The significance of the higher infection rate is unknown, but there is no clear reason why non-sterile gloves might be less effective in preventing infection in environments with lower infection rates.

This was not a double-blinded study, and physicians might change their behavior during a procedure depending on the type of gloves they are wearing. The sterile gloves used in this study contained powder, while the non-sterile gloves were powderless, but this variable is not known to affect infection rates. A study of Mohs surgery avoided this variable by only using powderless gloves, and had similar outcomes in terms of the difference in infection rate between sterile and non-sterile gloves.⁴

CHALLENGES TO IMPLEMENTATION:  Ingrained habits can be hard to change

Tradition and training die hard. While multiple studies in several settings have found non-sterile gloves are non-inferior to sterile gloves in preventing surgical site infection after minor skin surgeries, this single study in the primary care office setting may not be enough to sway family physicians from ingrained habits.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PRACTICE CHANGER
Consider prescribing oral naltrexone (50 mg/d) for patients with alcohol use disorder who wish to maintain abstinence after a brief period of detoxification.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis of 95 randomized controlled trials.¹

ILLUSTRATIVE CASE
Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for one of every 10 deaths among US adults ages 20 to 64.² About 20% to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that clinicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

Continue for study summary >>

STUDY SUMMARY
Evidence shows naltrexone can prevent a return to drinking
In a meta-analysis, Jonas et al¹ reviewed 123 studies (N = 22,803) of pharmacotherapy for AUD. After excluding 28 studies (seven were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized controlled trials were included in the analysis. Twenty-­two were placebo-controlled for acamprosate (1,000 to 3,000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and four compared the two drugs. Additional studies evaluated disulfiram as well as 23 other off-­label medications, such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk for bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias. 

Participants were primarily recruited as inpatients, and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least three days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of intervention varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed five drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥ 4 drinks/d for women and ≥ 5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 for acamprosate and 20 for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT, 12), while acamprosate did not. Neither medication showed a decrease in heavy drinking days.

In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk for bias and less effective in studies with a lower risk for bias. The two studies with the lowest risk for bias found no significant effect.

Disulfiram had no effect on any of the outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD], –6.5%), heavy drinking days (WMD, –9.0%), and drinks per drinking day (WMD, –1.0).

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk for diarrhea (number needed to harm [NNH], 11), vomiting (NNH, 42), and anxiety (NNH, 7). Naltrexone was associated with increased risk for nausea (NNH, 9), vomiting (NNH, 24), and dizziness (NNH, 16).

WHAT’S NEW
Consider prescribing naltrexone to prevent relapse
While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral nal­trexone. Prescribe oral naltrexone (50 mg/d) to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

Next page: Caveats >>

CAVEATS
Medication should be used with psychosocial treatments
Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and should be used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION
Cost, adherence may be factors for some patients
Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For clinicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Additionally, the medications are expensive. The branded version of naltrexone (50 mg) costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken three times a day. The risk for relapse is high until six to 12 months of sobriety is achieved and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of three months.⁵

REFERENCES
1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311:1889-1900.

2. CDC. Fact sheets - Alcohol use and your health. www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed April 13, 2015.

3. Johnson BA. Pharmacotherapy for alcohol use disorder. UpToDate. www.uptodate.com/contents/pharmacotherapy-for-alcohol-use-disorder. Accessed April 13, 2015.

4. US Preventive Services Task Force. Final recommendation statement: Alcohol misuse: Screening and behavioral counseling interventions in primary care. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/alcohol-misuse-screening-and-behavioral-counseling-interventions-in-primary-care. Accessed April 13, 2015.

5. US Department of Health and Human Services; National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism. Excerpt from Helping Patients Who Drink Too Much: A Clinician’s Guide. http://pubs.niaaa.nih.gov/publications/Practitioner/Clinicians Guide2005/PrescribingMeds.pdf. Accessed April 13, 2015.

6. Drugs.com. Revia prices, coupons and patient assistance programs. www.drugs.com/price-guide/revia. Accessed April 13, 2015.

7. Drugs.com. Campral prices, coupons and patient assistance programs. www.drugs.com/price-guide/campral. Accessed April 13, 2015.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. 

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(4):238-240.

PRACTICE CHANGER
Consider prescribing oral naltrexone (50 mg/d) for patients with alcohol use disorder who wish to maintain abstinence after a brief period of detoxification.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis of 95 randomized controlled trials.¹

ILLUSTRATIVE CASE
Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for one of every 10 deaths among US adults ages 20 to 64.² About 20% to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that clinicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

Continue for study summary >>

STUDY SUMMARY
Evidence shows naltrexone can prevent a return to drinking
In a meta-analysis, Jonas et al¹ reviewed 123 studies (N = 22,803) of pharmacotherapy for AUD. After excluding 28 studies (seven were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized controlled trials were included in the analysis. Twenty-­two were placebo-controlled for acamprosate (1,000 to 3,000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and four compared the two drugs. Additional studies evaluated disulfiram as well as 23 other off-­label medications, such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk for bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias. 

Participants were primarily recruited as inpatients, and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least three days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of intervention varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed five drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥ 4 drinks/d for women and ≥ 5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 for acamprosate and 20 for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT, 12), while acamprosate did not. Neither medication showed a decrease in heavy drinking days.

In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk for bias and less effective in studies with a lower risk for bias. The two studies with the lowest risk for bias found no significant effect.

Disulfiram had no effect on any of the outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD], –6.5%), heavy drinking days (WMD, –9.0%), and drinks per drinking day (WMD, –1.0).

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk for diarrhea (number needed to harm [NNH], 11), vomiting (NNH, 42), and anxiety (NNH, 7). Naltrexone was associated with increased risk for nausea (NNH, 9), vomiting (NNH, 24), and dizziness (NNH, 16).

WHAT’S NEW
Consider prescribing naltrexone to prevent relapse
While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral nal­trexone. Prescribe oral naltrexone (50 mg/d) to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

Next page: Caveats >>

CAVEATS
Medication should be used with psychosocial treatments
Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and should be used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION
Cost, adherence may be factors for some patients
Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For clinicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Additionally, the medications are expensive. The branded version of naltrexone (50 mg) costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken three times a day. The risk for relapse is high until six to 12 months of sobriety is achieved and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of three months.⁵

REFERENCES
1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311:1889-1900.

2. CDC. Fact sheets - Alcohol use and your health. www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed April 13, 2015.

3. Johnson BA. Pharmacotherapy for alcohol use disorder. UpToDate. www.uptodate.com/contents/pharmacotherapy-for-alcohol-use-disorder. Accessed April 13, 2015.

4. US Preventive Services Task Force. Final recommendation statement: Alcohol misuse: Screening and behavioral counseling interventions in primary care. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/alcohol-misuse-screening-and-behavioral-counseling-interventions-in-primary-care. Accessed April 13, 2015.

5. US Department of Health and Human Services; National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism. Excerpt from Helping Patients Who Drink Too Much: A Clinician’s Guide. http://pubs.niaaa.nih.gov/publications/Practitioner/Clinicians Guide2005/PrescribingMeds.pdf. Accessed April 13, 2015.

6. Drugs.com. Revia prices, coupons and patient assistance programs. www.drugs.com/price-guide/revia. Accessed April 13, 2015.

7. Drugs.com. Campral prices, coupons and patient assistance programs. www.drugs.com/price-guide/campral. Accessed April 13, 2015.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. 

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(4):238-240.

PRACTICE CHANGER
Consider prescribing oral naltrexone (50 mg/d) for patients with alcohol use disorder who wish to maintain abstinence after a brief period of detoxification.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis of 95 randomized controlled trials.¹

ILLUSTRATIVE CASE
Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for one of every 10 deaths among US adults ages 20 to 64.² About 20% to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that clinicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

Continue for study summary >>

STUDY SUMMARY
Evidence shows naltrexone can prevent a return to drinking
In a meta-analysis, Jonas et al¹ reviewed 123 studies (N = 22,803) of pharmacotherapy for AUD. After excluding 28 studies (seven were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized controlled trials were included in the analysis. Twenty-­two were placebo-controlled for acamprosate (1,000 to 3,000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and four compared the two drugs. Additional studies evaluated disulfiram as well as 23 other off-­label medications, such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk for bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias. 

Participants were primarily recruited as inpatients, and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least three days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of intervention varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed five drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥ 4 drinks/d for women and ≥ 5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 for acamprosate and 20 for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT, 12), while acamprosate did not. Neither medication showed a decrease in heavy drinking days.

In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk for bias and less effective in studies with a lower risk for bias. The two studies with the lowest risk for bias found no significant effect.

Disulfiram had no effect on any of the outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD], –6.5%), heavy drinking days (WMD, –9.0%), and drinks per drinking day (WMD, –1.0).

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk for diarrhea (number needed to harm [NNH], 11), vomiting (NNH, 42), and anxiety (NNH, 7). Naltrexone was associated with increased risk for nausea (NNH, 9), vomiting (NNH, 24), and dizziness (NNH, 16).

WHAT’S NEW
Consider prescribing naltrexone to prevent relapse
While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral nal­trexone. Prescribe oral naltrexone (50 mg/d) to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

Next page: Caveats >>

CAVEATS
Medication should be used with psychosocial treatments
Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and should be used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION
Cost, adherence may be factors for some patients
Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For clinicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Additionally, the medications are expensive. The branded version of naltrexone (50 mg) costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken three times a day. The risk for relapse is high until six to 12 months of sobriety is achieved and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of three months.⁵

REFERENCES
1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311:1889-1900.

2. CDC. Fact sheets - Alcohol use and your health. www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed April 13, 2015.

3. Johnson BA. Pharmacotherapy for alcohol use disorder. UpToDate. www.uptodate.com/contents/pharmacotherapy-for-alcohol-use-disorder. Accessed April 13, 2015.

4. US Preventive Services Task Force. Final recommendation statement: Alcohol misuse: Screening and behavioral counseling interventions in primary care. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/alcohol-misuse-screening-and-behavioral-counseling-interventions-in-primary-care. Accessed April 13, 2015.

5. US Department of Health and Human Services; National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism. Excerpt from Helping Patients Who Drink Too Much: A Clinician’s Guide. http://pubs.niaaa.nih.gov/publications/Practitioner/Clinicians Guide2005/PrescribingMeds.pdf. Accessed April 13, 2015.

6. Drugs.com. Revia prices, coupons and patient assistance programs. www.drugs.com/price-guide/revia. Accessed April 13, 2015.

7. Drugs.com. Campral prices, coupons and patient assistance programs. www.drugs.com/price-guide/campral. Accessed April 13, 2015.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. 

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(4):238-240.

Illustrative case

Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking, but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for 1 of every 10 deaths among US adults ages 20 to 64 years.² Twenty percent to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

Listen to Shannon Robinson, MD discuss: Sobriety meds—A look at compliance and cost

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that physicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

STUDY SUMMARY: Evidence shows naltrexone can prevent a return to drinking

In a meta-analysis, Jonas et al¹ reviewed 123 studies (N=22,803) of pharmacotherapy for AUD. After excluding 28 studies (7 were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized control trials were included in the analysis. Twenty-two were placebo-controlled for acamprosate (1000-3000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and 4 compared the 2 drugs. Additional studies evaluated disulfiram as well as 23 other off-label medications such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk of bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias.

Participants were primarily recruited as inpatients and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least 3 days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of interventions varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed 5 drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥4 drinks/d for women and ≥5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 (95% confidence interval [CI], 8-26) for acamprosate and 20 (95% CI, 11-500) for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT=12; 95% CI, 8-26), while acamprosate did not. Neither medication showed a decrease in heavy drinking days. In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk of bias and less effective in studies with a lower risk of bias; the 2 studies with the lowest risk of bias found no significant effect.

Disulfiram had no effect on any of the drinking outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD]=-6.5%; 95% CI, -12.0% to -1.0%), heavy drinking days (WMD=-9.0%; 95% CI, -15.3% to -2.7%), and drinks per drinking day (WMD=-1.0; 95% CI, -1.6 to -0.48).

Oral naltrexone 50 mg/d significantly decreased the number of patients who resumed drinking after detoxification.

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk of diarrhea (number needed to harm [NNH]=11; 95% CI, 6-34), vomiting (NNH=42; 95% CI, 24-143), and anxiety (NNH=7; 95% CI, 5-11). Naltrexone was associated with increased risk of nausea (NNH=9; 95% CI, 7-14), vomiting (NNH=24; 95% CI, 17-44), and dizziness (NNH 16; 95% CI, 12-28).

WHAT'S NEW: Consider prescribing naltrexone to prevent relapse

While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral naltrexone. Prescribe oral naltrexone 50 mg/d to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

CAVEATS: Medication should be used with psychosocial treatments

Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure, and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION: Cost, adherence may be factors for some patients 

Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For physicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Medications for alcohol use disorder should be reserved for patients who want to quit drinking, and should be combined with psychosocial interventions.

Additionally, the medications are expensive. The branded version of naltrexone 50 mg costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken 3 times a day. The risk of relapse is high until 6 to 12 months of sobriety and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of 3 months.⁵

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking, but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for 1 of every 10 deaths among US adults ages 20 to 64 years.² Twenty percent to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

Listen to Shannon Robinson, MD discuss: Sobriety meds—A look at compliance and cost

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that physicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

STUDY SUMMARY: Evidence shows naltrexone can prevent a return to drinking

In a meta-analysis, Jonas et al¹ reviewed 123 studies (N=22,803) of pharmacotherapy for AUD. After excluding 28 studies (7 were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized control trials were included in the analysis. Twenty-two were placebo-controlled for acamprosate (1000-3000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and 4 compared the 2 drugs. Additional studies evaluated disulfiram as well as 23 other off-label medications such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk of bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias.

Participants were primarily recruited as inpatients and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least 3 days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of interventions varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed 5 drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥4 drinks/d for women and ≥5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 (95% confidence interval [CI], 8-26) for acamprosate and 20 (95% CI, 11-500) for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT=12; 95% CI, 8-26), while acamprosate did not. Neither medication showed a decrease in heavy drinking days. In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk of bias and less effective in studies with a lower risk of bias; the 2 studies with the lowest risk of bias found no significant effect.

Disulfiram had no effect on any of the drinking outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD]=-6.5%; 95% CI, -12.0% to -1.0%), heavy drinking days (WMD=-9.0%; 95% CI, -15.3% to -2.7%), and drinks per drinking day (WMD=-1.0; 95% CI, -1.6 to -0.48).

Oral naltrexone 50 mg/d significantly decreased the number of patients who resumed drinking after detoxification.

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk of diarrhea (number needed to harm [NNH]=11; 95% CI, 6-34), vomiting (NNH=42; 95% CI, 24-143), and anxiety (NNH=7; 95% CI, 5-11). Naltrexone was associated with increased risk of nausea (NNH=9; 95% CI, 7-14), vomiting (NNH=24; 95% CI, 17-44), and dizziness (NNH 16; 95% CI, 12-28).

WHAT'S NEW: Consider prescribing naltrexone to prevent relapse

While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral naltrexone. Prescribe oral naltrexone 50 mg/d to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

CAVEATS: Medication should be used with psychosocial treatments

Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure, and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION: Cost, adherence may be factors for some patients 

Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For physicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Medications for alcohol use disorder should be reserved for patients who want to quit drinking, and should be combined with psychosocial interventions.

Additionally, the medications are expensive. The branded version of naltrexone 50 mg costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken 3 times a day. The risk of relapse is high until 6 to 12 months of sobriety and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of 3 months.⁵

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

Your patient, a 42-year-old man with alcohol use disorder (AUD), detoxifies from alcohol during a recent hospitalization. He doesn’t want to resume drinking, but reports frequent cravings. Are there any medications you can prescribe to help prevent relapse?

Excessive alcohol consumption is responsible for 1 of every 10 deaths among US adults ages 20 to 64 years.² Twenty percent to 36% of patients seen in a primary care office have AUD.³ Up to 70% of people who quit with psychosocial support alone will relapse.³

Listen to Shannon Robinson, MD discuss: Sobriety meds—A look at compliance and cost

The US Preventive Services Task Force gives a grade B recommendation to screening all adults for AUD, indicating that physicians should provide this service.⁴ For patients with AUD who wish to abstain but struggle with cravings and relapse, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommends considering medication as an adjunct to brief behavioral counseling.⁵

STUDY SUMMARY: Evidence shows naltrexone can prevent a return to drinking

In a meta-analysis, Jonas et al¹ reviewed 123 studies (N=22,803) of pharmacotherapy for AUD. After excluding 28 studies (7 were the only study of a given drug, one was a prospective cohort, and 20 had insufficient data), 95 randomized control trials were included in the analysis. Twenty-two were placebo-controlled for acamprosate (1000-3000 mg/d), 44 for naltrexone (50 mg/d oral, 100 mg/d oral, or injectable) and 4 compared the 2 drugs. Additional studies evaluated disulfiram as well as 23 other off-label medications such as valproic acid and topiramate.

Two investigators independently reviewed the studies, checking for completeness and accuracy. Studies were also analyzed for bias using predefined criteria; those with high or unclear risk of bias were excluded from the main analysis but included in the sensitivity analysis. Funnel plots showed no evidence of publication bias.

Participants were primarily recruited as inpatients and in most studies the mean age was in the 40s. Most patients were diagnosed with alcohol dependence based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR); this diagnosis translates to likely moderate to severe AUD in DSM-5. Prior to starting medications, participants underwent detoxification or achieved at least 3 days of sobriety. Most studies included psychosocial intervention in addition to medication, but the types of interventions varied. The duration of the trials ranged from 12 to 52 weeks.

Researchers analyzed 5 drinking outcomes—return to any drinking, return to heavy drinking (defined as ≥4 drinks/d for women and ≥5 drinks/d for men), number of drinking days, number of heavy drinking days, and drinks per drinking day. They also evaluated health outcomes (accidents, injuries, quality of life, function, and mortality) and adverse effects.

Acamprosate and oral naltrexone (50 mg/d) significantly decreased return to any drinking, with a number needed to treat (NNT) of 12 (95% confidence interval [CI], 8-26) for acamprosate and 20 (95% CI, 11-500) for naltrexone. Oral naltrexone (50 mg/d) also decreased return to heavy drinking (NNT=12; 95% CI, 8-26), while acamprosate did not. Neither medication showed a decrease in heavy drinking days. In a post hoc subgroup analysis of acamprosate for return to any drinking, the drug appeared to be more effective in studies with a higher risk of bias and less effective in studies with a lower risk of bias; the 2 studies with the lowest risk of bias found no significant effect.

Disulfiram had no effect on any of the drinking outcomes analyzed.

Of the off-label medications, topiramate showed a decrease in drinking days (weighted mean difference [WMD]=-6.5%; 95% CI, -12.0% to -1.0%), heavy drinking days (WMD=-9.0%; 95% CI, -15.3% to -2.7%), and drinks per drinking day (WMD=-1.0; 95% CI, -1.6 to -0.48).

Oral naltrexone 50 mg/d significantly decreased the number of patients who resumed drinking after detoxification.

There were no significant differences in health outcomes for any of the medications. Adverse events were greater in treatment groups than placebo groups. Acamprosate was associated with increased risk of diarrhea (number needed to harm [NNH]=11; 95% CI, 6-34), vomiting (NNH=42; 95% CI, 24-143), and anxiety (NNH=7; 95% CI, 5-11). Naltrexone was associated with increased risk of nausea (NNH=9; 95% CI, 7-14), vomiting (NNH=24; 95% CI, 17-44), and dizziness (NNH 16; 95% CI, 12-28).

WHAT'S NEW: Consider prescribing naltrexone to prevent relapse

While previous studies suggested that pharmacotherapy could help patients with AUD remain abstinent, this methodologically rigorous meta-analysis compared the efficacy of several commonly used medications and found clear evidence favoring oral naltrexone. Prescribe oral naltrexone 50 mg/d to help patients with moderate to severe AUD avoid returning to any drinking or heavy drinking after alcohol detoxification. Acamprosate may also decrease return to drinking, although the evidence is not as strong (the studies with low bias showed no effect).

CAVEATS: Medication should be used with psychosocial treatments

Pharmacotherapy for AUD should be reserved for patients who want to quit drinking and used in conjunction with psychosocial intervention.³ Only one of the studies analyzed by Jonas et al¹ was conducted in primary care. That said, many of the psychosocial interventions—such as regular follow-up visits to encourage adherence and monitor for adverse effects, in conjunction with attendance at Alcoholics Anonymous meetings—could be done in primary care settings.

Comorbidities may limit therapy options. Naltrexone is contraindicated in acute hepatitis and liver failure, and in combination with opioids.⁵ Acamprosate is contraindicated in renal disease.⁵

CHALLENGES TO IMPLEMENTATION: Cost, adherence may be factors for some patients 

Perhaps the greatest hurdle in pharmacotherapy for AUD in primary care is a lack of familiarity with these medications. For physicians who are comfortable with prescribing these medications, implementation may be hindered by a lack of available psychosocial resources for successful abstinence.

Medications for alcohol use disorder should be reserved for patients who want to quit drinking, and should be combined with psychosocial interventions.

Additionally, the medications are expensive. The branded version of naltrexone 50 mg costs approximately $118 for a 30-day supply,⁶ and the branded version of acamprosate costs approximately $284 for a 30-day supply.⁷

As is the case with any chronic medical condition, medication adherence is a challenge. Naltrexone is taken once daily, while acamprosate is taken 3 times a day. The risk of relapse is high until 6 to 12 months of sobriety and then wanes over several years.⁵ The NIAAA recommends treatment for a minimum of 3 months.⁵

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 40-year-old man comes to your office for follow-up of medial left knee pain he’s had for 3 months that hasn’t responded to conservative treatment. The pain developed gradually, without a history of trauma. The patient has no signs of degenerative joint disease on x-ray but magnetic resonance imaging (MRI) reveals a tear of the medial meniscus. Should you refer him for meniscectomy?

Patients and doctors alike tend to look for a treatment that will “fix” the problem, which may be why we have continued to use arthroscopic partial meniscectomy to attempt to relieve symptoms of meniscal tears despite a lack of evidence to support the practice.

Guidelines from the American Academy of Orthopaedic Surgeons state that the evidence for medial meniscectomy in patients with a torn meniscus and osteoarthritis (OA) is inconclusive; the organization offers no guidelines for patients with a torn meniscus who don’t have OA.² The American College of Occupational and Environmental Medicine states that there is insufficient evidence to support arthroscopic partial meniscectomy for symptomatic, torn medial menisci for select patients and “the vast majority of patients [with medial meniscal tears] do not require surgery.”³ Previous studies have concluded that arthroscopic surgery for OA of the knee provides no additional benefit to optimized physical and medical therapy.⁴ Furthermore, research by Katz et al⁵ shows that meniscectomy provides no benefit over conservative treatment in functional status at 6 months in patients with OA and a medial meniscal tear.

That said, arthroscopic partial meniscectomy is still the most common orthopedic procedure in the United States.¹ Although its use has decreased over the last 15 years, it is performed nearly 700,000 times annually at a cost of approximately $4 billion.^1,6,7 Like any surgical procedure, meniscectomy carries a risk of complications. In the double-blind, randomized trial reported on here, Sihvonen et al¹ compared meniscectomy to a sham procedure for patients with knee pain, but not OA.

STUDY SUMMARY: Meniscectomy and sham surgery 
are equally effective


Sihvonen et al¹ conducted a randomized, double-blind, sham-controlled trial at 5 orthopedic clinics in Finland. Patients ages 35 to 65 years were enrolled if they had clinical findings of a medial meniscus tear and knee pain for >3 months that wasn’t relieved by conservative treatment. The trial excluded patients who had an obvious traumatic onset of symptoms; clinical or radiological evidence of knee OA; a locked knee that could not be straightened; knee instability or decreased range of motion; previous surgery on the affected knee; fracture within the past 12 months on the affected limb; or other notable pathology on MRI or during arthroscopy.

Before randomization, 160 patients underwent diagnostic arthroscopy. Fourteen patients were excluded: 6 because they did not actually have a medial meniscal tear, one because he also had a lateral meniscus tear, 3 due to a major chondral flap, 2 who had already undergone meniscal repair, and 2 due to an osteochondral microfracture.

At the end of the diagnostic arthroscopy, each patient was blindly randomized to arthroscopic partial meniscectomy or sham surgery. To simulate the meniscectomy procedure, the surgeon similarly manipulated the knee, made comparable noise and vibration using tools and suction, and ensured that the patient was kept in the operating room (OR) for a comparable time. Only the orthopedic surgeon and OR staff were aware of which surgery the patient underwent, and these staff members were not included in further treatment or follow-up. After the procedure, all patients received the same walking aids and instructions for a graduated exercise program.

The 70 patients in the meniscectomy group and the 76 in the sham surgery group were similar in age (mean: 52 years), sex, body mass index, and duration of pain (mean: 10 months). Patients in both groups also had similar tears noted on arthroscopy.

Three primary outcomes were measured before surgery and at 12 months: knee pain, knee symptoms and function, and quality of life. Knee pain after exercise was evaluated on a 0 to 10 scale, with 0 indicating no pain. The validated Lysholm knee score was used to assess knee symptoms and function and the Western Ontario Meniscal Evaluation Tool (WOMET) was utilized to evaluate quality of life; both are 100-point scales in which lower scores indicate more severe symptoms.

Both groups had marked improvement in pain and function from baseline to 12 months, and there was no significant difference between the 2 groups. Knee pain scores improved by 3.1 in the meniscectomy group and 3.3 in the sham surgery group.


Lysholm symptom and function scores improved 21.7 points in the meniscectomy group and 23.3 points in the sham surgery group (a change of 11.5 points would have been considered clinically significant). The mean between-group difference was -1.6 points (95% confidence interval [CI], -7.2 to 4.0).

Both meniscectomy and sham surgery led
 to marked improvement at 12 months, with no significant differences in outcomes. WOMET quality of life scores improved 24.6 points in the meniscectomy group and 27.1 points in the sham surgery (a change of 15.5 points would have been considered clinically significant). The mean between-group difference was -2.5 points (95% CI, -9.2 to 4.1).

There were no significant between-group differences in serious adverse events or number of patients who required subsequent knee surgery. Similar proportions in each group thought they had sham surgery, which confirmed the effectiveness of the blinding. Ninety-six percent of patients in the sham procedure group and 93% in the meniscectomy group reported they would be willing to repeat the procedure.

WHAT'S NEW: Recommend physical therapy,
 exercise instead of surgery


Previous studies of arthroscopic partial meniscectomy to treat degenerative meniscal tears in patients with knee OA found no benefit.^6,8 This study specifically examined patients without OA and found arthroscopic partial meniscectomy offered no benefit over sham surgery.

In addition to fewer referrals for meniscectomy, these findings could lead to another change in practice: Physicians may be less likely to order an MRI to confirm the diagnosis of a medial meniscal tear, since doing so will not change their therapeutic approach. This approach centers on recommending that patients with a degenerative meniscal tear start and stick with physical therapy and their designated exercise regimen.

CAVEATS: Surgery might be effective for more active patients

This study, as well as previous research, did not look at surgery for an acute medial meniscus tear following a traumatic incident, such as a fall or direct blow. Additionally, these results are based on improved outcomes in activities of daily living, and may not extend to patients who engage in high-level functioning, such as sports or strenuous work. The sham surgery group received lavage, which could be considered an active treatment, although a previous trial found lavage had no benefit over conservative treatment in patients with knee OA.⁴

CHALLENGES TO IMPLEMENTATION: It might be hard to convince patients they don’t need surgery

Some patients expect immediate intervention with surgery. It may be difficult to convince such patients that active participation in physical therapy can lead to the same outcomes as surgery. Spending time with your patient to explain the injury, what happens during surgery, and the evidence that shows a lack of difference in outcomes can lead to fewer surgeries. Most patients and physicians will want to do an MRI after 3 months of persistent pain to determine the diagnosis, although some may be comfortable with continuing conservative treatment.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

A 40-year-old man comes to your office for follow-up of medial left knee pain he’s had for 3 months that hasn’t responded to conservative treatment. The pain developed gradually, without a history of trauma. The patient has no signs of degenerative joint disease on x-ray but magnetic resonance imaging (MRI) reveals a tear of the medial meniscus. Should you refer him for meniscectomy?

Patients and doctors alike tend to look for a treatment that will “fix” the problem, which may be why we have continued to use arthroscopic partial meniscectomy to attempt to relieve symptoms of meniscal tears despite a lack of evidence to support the practice.

Guidelines from the American Academy of Orthopaedic Surgeons state that the evidence for medial meniscectomy in patients with a torn meniscus and osteoarthritis (OA) is inconclusive; the organization offers no guidelines for patients with a torn meniscus who don’t have OA.² The American College of Occupational and Environmental Medicine states that there is insufficient evidence to support arthroscopic partial meniscectomy for symptomatic, torn medial menisci for select patients and “the vast majority of patients [with medial meniscal tears] do not require surgery.”³ Previous studies have concluded that arthroscopic surgery for OA of the knee provides no additional benefit to optimized physical and medical therapy.⁴ Furthermore, research by Katz et al⁵ shows that meniscectomy provides no benefit over conservative treatment in functional status at 6 months in patients with OA and a medial meniscal tear.

That said, arthroscopic partial meniscectomy is still the most common orthopedic procedure in the United States.¹ Although its use has decreased over the last 15 years, it is performed nearly 700,000 times annually at a cost of approximately $4 billion.^1,6,7 Like any surgical procedure, meniscectomy carries a risk of complications. In the double-blind, randomized trial reported on here, Sihvonen et al¹ compared meniscectomy to a sham procedure for patients with knee pain, but not OA.

STUDY SUMMARY: Meniscectomy and sham surgery 
are equally effective


Sihvonen et al¹ conducted a randomized, double-blind, sham-controlled trial at 5 orthopedic clinics in Finland. Patients ages 35 to 65 years were enrolled if they had clinical findings of a medial meniscus tear and knee pain for >3 months that wasn’t relieved by conservative treatment. The trial excluded patients who had an obvious traumatic onset of symptoms; clinical or radiological evidence of knee OA; a locked knee that could not be straightened; knee instability or decreased range of motion; previous surgery on the affected knee; fracture within the past 12 months on the affected limb; or other notable pathology on MRI or during arthroscopy.

Before randomization, 160 patients underwent diagnostic arthroscopy. Fourteen patients were excluded: 6 because they did not actually have a medial meniscal tear, one because he also had a lateral meniscus tear, 3 due to a major chondral flap, 2 who had already undergone meniscal repair, and 2 due to an osteochondral microfracture.

At the end of the diagnostic arthroscopy, each patient was blindly randomized to arthroscopic partial meniscectomy or sham surgery. To simulate the meniscectomy procedure, the surgeon similarly manipulated the knee, made comparable noise and vibration using tools and suction, and ensured that the patient was kept in the operating room (OR) for a comparable time. Only the orthopedic surgeon and OR staff were aware of which surgery the patient underwent, and these staff members were not included in further treatment or follow-up. After the procedure, all patients received the same walking aids and instructions for a graduated exercise program.

The 70 patients in the meniscectomy group and the 76 in the sham surgery group were similar in age (mean: 52 years), sex, body mass index, and duration of pain (mean: 10 months). Patients in both groups also had similar tears noted on arthroscopy.

Three primary outcomes were measured before surgery and at 12 months: knee pain, knee symptoms and function, and quality of life. Knee pain after exercise was evaluated on a 0 to 10 scale, with 0 indicating no pain. The validated Lysholm knee score was used to assess knee symptoms and function and the Western Ontario Meniscal Evaluation Tool (WOMET) was utilized to evaluate quality of life; both are 100-point scales in which lower scores indicate more severe symptoms.

Both groups had marked improvement in pain and function from baseline to 12 months, and there was no significant difference between the 2 groups. Knee pain scores improved by 3.1 in the meniscectomy group and 3.3 in the sham surgery group.


Lysholm symptom and function scores improved 21.7 points in the meniscectomy group and 23.3 points in the sham surgery group (a change of 11.5 points would have been considered clinically significant). The mean between-group difference was -1.6 points (95% confidence interval [CI], -7.2 to 4.0).

Both meniscectomy and sham surgery led
 to marked improvement at 12 months, with no significant differences in outcomes. WOMET quality of life scores improved 24.6 points in the meniscectomy group and 27.1 points in the sham surgery (a change of 15.5 points would have been considered clinically significant). The mean between-group difference was -2.5 points (95% CI, -9.2 to 4.1).

There were no significant between-group differences in serious adverse events or number of patients who required subsequent knee surgery. Similar proportions in each group thought they had sham surgery, which confirmed the effectiveness of the blinding. Ninety-six percent of patients in the sham procedure group and 93% in the meniscectomy group reported they would be willing to repeat the procedure.

WHAT'S NEW: Recommend physical therapy,
 exercise instead of surgery


Previous studies of arthroscopic partial meniscectomy to treat degenerative meniscal tears in patients with knee OA found no benefit.^6,8 This study specifically examined patients without OA and found arthroscopic partial meniscectomy offered no benefit over sham surgery.

In addition to fewer referrals for meniscectomy, these findings could lead to another change in practice: Physicians may be less likely to order an MRI to confirm the diagnosis of a medial meniscal tear, since doing so will not change their therapeutic approach. This approach centers on recommending that patients with a degenerative meniscal tear start and stick with physical therapy and their designated exercise regimen.

CAVEATS: Surgery might be effective for more active patients

This study, as well as previous research, did not look at surgery for an acute medial meniscus tear following a traumatic incident, such as a fall or direct blow. Additionally, these results are based on improved outcomes in activities of daily living, and may not extend to patients who engage in high-level functioning, such as sports or strenuous work. The sham surgery group received lavage, which could be considered an active treatment, although a previous trial found lavage had no benefit over conservative treatment in patients with knee OA.⁴

CHALLENGES TO IMPLEMENTATION: It might be hard to convince patients they don’t need surgery

Some patients expect immediate intervention with surgery. It may be difficult to convince such patients that active participation in physical therapy can lead to the same outcomes as surgery. Spending time with your patient to explain the injury, what happens during surgery, and the evidence that shows a lack of difference in outcomes can lead to fewer surgeries. Most patients and physicians will want to do an MRI after 3 months of persistent pain to determine the diagnosis, although some may be comfortable with continuing conservative treatment.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Illustrative case

A 40-year-old man comes to your office for follow-up of medial left knee pain he’s had for 3 months that hasn’t responded to conservative treatment. The pain developed gradually, without a history of trauma. The patient has no signs of degenerative joint disease on x-ray but magnetic resonance imaging (MRI) reveals a tear of the medial meniscus. Should you refer him for meniscectomy?

Patients and doctors alike tend to look for a treatment that will “fix” the problem, which may be why we have continued to use arthroscopic partial meniscectomy to attempt to relieve symptoms of meniscal tears despite a lack of evidence to support the practice.

Guidelines from the American Academy of Orthopaedic Surgeons state that the evidence for medial meniscectomy in patients with a torn meniscus and osteoarthritis (OA) is inconclusive; the organization offers no guidelines for patients with a torn meniscus who don’t have OA.² The American College of Occupational and Environmental Medicine states that there is insufficient evidence to support arthroscopic partial meniscectomy for symptomatic, torn medial menisci for select patients and “the vast majority of patients [with medial meniscal tears] do not require surgery.”³ Previous studies have concluded that arthroscopic surgery for OA of the knee provides no additional benefit to optimized physical and medical therapy.⁴ Furthermore, research by Katz et al⁵ shows that meniscectomy provides no benefit over conservative treatment in functional status at 6 months in patients with OA and a medial meniscal tear.

That said, arthroscopic partial meniscectomy is still the most common orthopedic procedure in the United States.¹ Although its use has decreased over the last 15 years, it is performed nearly 700,000 times annually at a cost of approximately $4 billion.^1,6,7 Like any surgical procedure, meniscectomy carries a risk of complications. In the double-blind, randomized trial reported on here, Sihvonen et al¹ compared meniscectomy to a sham procedure for patients with knee pain, but not OA.

STUDY SUMMARY: Meniscectomy and sham surgery 
are equally effective


Sihvonen et al¹ conducted a randomized, double-blind, sham-controlled trial at 5 orthopedic clinics in Finland. Patients ages 35 to 65 years were enrolled if they had clinical findings of a medial meniscus tear and knee pain for >3 months that wasn’t relieved by conservative treatment. The trial excluded patients who had an obvious traumatic onset of symptoms; clinical or radiological evidence of knee OA; a locked knee that could not be straightened; knee instability or decreased range of motion; previous surgery on the affected knee; fracture within the past 12 months on the affected limb; or other notable pathology on MRI or during arthroscopy.

Before randomization, 160 patients underwent diagnostic arthroscopy. Fourteen patients were excluded: 6 because they did not actually have a medial meniscal tear, one because he also had a lateral meniscus tear, 3 due to a major chondral flap, 2 who had already undergone meniscal repair, and 2 due to an osteochondral microfracture.

At the end of the diagnostic arthroscopy, each patient was blindly randomized to arthroscopic partial meniscectomy or sham surgery. To simulate the meniscectomy procedure, the surgeon similarly manipulated the knee, made comparable noise and vibration using tools and suction, and ensured that the patient was kept in the operating room (OR) for a comparable time. Only the orthopedic surgeon and OR staff were aware of which surgery the patient underwent, and these staff members were not included in further treatment or follow-up. After the procedure, all patients received the same walking aids and instructions for a graduated exercise program.

The 70 patients in the meniscectomy group and the 76 in the sham surgery group were similar in age (mean: 52 years), sex, body mass index, and duration of pain (mean: 10 months). Patients in both groups also had similar tears noted on arthroscopy.

Three primary outcomes were measured before surgery and at 12 months: knee pain, knee symptoms and function, and quality of life. Knee pain after exercise was evaluated on a 0 to 10 scale, with 0 indicating no pain. The validated Lysholm knee score was used to assess knee symptoms and function and the Western Ontario Meniscal Evaluation Tool (WOMET) was utilized to evaluate quality of life; both are 100-point scales in which lower scores indicate more severe symptoms.

Both groups had marked improvement in pain and function from baseline to 12 months, and there was no significant difference between the 2 groups. Knee pain scores improved by 3.1 in the meniscectomy group and 3.3 in the sham surgery group.


Lysholm symptom and function scores improved 21.7 points in the meniscectomy group and 23.3 points in the sham surgery group (a change of 11.5 points would have been considered clinically significant). The mean between-group difference was -1.6 points (95% confidence interval [CI], -7.2 to 4.0).

Both meniscectomy and sham surgery led
 to marked improvement at 12 months, with no significant differences in outcomes. WOMET quality of life scores improved 24.6 points in the meniscectomy group and 27.1 points in the sham surgery (a change of 15.5 points would have been considered clinically significant). The mean between-group difference was -2.5 points (95% CI, -9.2 to 4.1).

There were no significant between-group differences in serious adverse events or number of patients who required subsequent knee surgery. Similar proportions in each group thought they had sham surgery, which confirmed the effectiveness of the blinding. Ninety-six percent of patients in the sham procedure group and 93% in the meniscectomy group reported they would be willing to repeat the procedure.

WHAT'S NEW: Recommend physical therapy,
 exercise instead of surgery


Previous studies of arthroscopic partial meniscectomy to treat degenerative meniscal tears in patients with knee OA found no benefit.^6,8 This study specifically examined patients without OA and found arthroscopic partial meniscectomy offered no benefit over sham surgery.

In addition to fewer referrals for meniscectomy, these findings could lead to another change in practice: Physicians may be less likely to order an MRI to confirm the diagnosis of a medial meniscal tear, since doing so will not change their therapeutic approach. This approach centers on recommending that patients with a degenerative meniscal tear start and stick with physical therapy and their designated exercise regimen.

CAVEATS: Surgery might be effective for more active patients

This study, as well as previous research, did not look at surgery for an acute medial meniscus tear following a traumatic incident, such as a fall or direct blow. Additionally, these results are based on improved outcomes in activities of daily living, and may not extend to patients who engage in high-level functioning, such as sports or strenuous work. The sham surgery group received lavage, which could be considered an active treatment, although a previous trial found lavage had no benefit over conservative treatment in patients with knee OA.⁴

CHALLENGES TO IMPLEMENTATION: It might be hard to convince patients they don’t need surgery

Some patients expect immediate intervention with surgery. It may be difficult to convince such patients that active participation in physical therapy can lead to the same outcomes as surgery. Spending time with your patient to explain the injury, what happens during surgery, and the evidence that shows a lack of difference in outcomes can lead to fewer surgeries. Most patients and physicians will want to do an MRI after 3 months of persistent pain to determine the diagnosis, although some may be comfortable with continuing conservative treatment.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

PRACTICE CHANGER

Do not routinely initiate β-blockers in patients undergoing intermediate- or high-risk noncardiac surgery. β-Blockers appear to increase the 30-day risk for all-cause mortality.¹

STRENGTH OF RECOMMENDATION

A: Based on meta-analysis of nine randomized controlled trials (RCTs).¹

ILLUSTRATIVE CASE
A 67-year-old woman with diabetes, hypertension, and hyperlipidemia presents for evaluation prior to a total hip arthroplasty. She is not taking a β-blocker. Should you prescribe one?

Study summary >>

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting 

β-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials. These trials  have been discredited due to serious methodologic flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³

A new meta-analysis conducted by Bouri et al¹ that excluded the DECREASE trials found that, although preoperative β-blockers reduce the rate of certain nonfatal outcomes, they increase the risk for death and stroke.

STUDY SUMMARY
Preop β-blockers do more harm than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative β-blockers versus placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, two were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed nine high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgic, orthopedic, urologic, and gynecologic surgeries. β-Blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in five trials, bisoprolol in one trial, atenolol in two trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5,264 patients were randomly assigned to receive β-blockers and 5,265 to placebo. There were 162 deaths in the β-blocker group and 129 deaths in the placebo group. Patients who received β-blockers had a 27% increased risk for all-cause mortality (risk ratio [RR] = 1.27). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal MI, nonfatal stroke, and hypotension. β-Blockers lowered the risk for nonfatal MI (RR = 0.73) but increased the risk for nonfatal stroke (RR = 1.73) and hypotension (RR = 1.51).

This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol (100 mg 2 to 4 h before surgery, followed by 200 mg/d for 30 d), in 8,351 patients with, or at risk for, atherosclerotic disease.⁴ While β-blockers reduced the risk for MI and atrial fibrillation, they increased the risk for mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of β-blockers used in this study may have contributed to the excess mortality.

What's new and challenges to implementation >> 

WHAT’S NEW
Avoiding β-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while β-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of β-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate- or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if β-blockers were not used.¹

CAVEATS
Don’t stop β-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking β-blockers. These patients should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION
Reluctance to disregard published guidelines 
Some clinicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIA recommendation (it is reasonable to administer this treatment) for the use of preoperative β-blockade for patients at risk for cardiovascular events who were not previously taking a β-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we await updated recommendations.       

REFERENCES
1. Bouri S, Shun-Shin MJ, Cole GD, et al. Meta-analysis of secure randomised controlled trials of ß-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014;100:456-464.

2. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine; Society for Vascular Surgery; Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. J Am Coll Cardiol. 2009;54:e13-e118.

3. Erasmus Medical Center Follow-up Investigation Committee. Report on the 2012 follow-up investigation of possible breaches of academic integrity (September 30, 2012). CardioBrief. Available at: http://cardiobrief.files.wordpress.com/2012/10/integrity-report-2012-10-english-translation.pdf. Accessed August 14, 2014.

4. Devereaux PJ, Yang H, Yusuf S, et al; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;
371:1839-1847.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(6):E15-E16.

PRACTICE CHANGER

Do not routinely initiate β-blockers in patients undergoing intermediate- or high-risk noncardiac surgery. β-Blockers appear to increase the 30-day risk for all-cause mortality.¹

STRENGTH OF RECOMMENDATION

A: Based on meta-analysis of nine randomized controlled trials (RCTs).¹

ILLUSTRATIVE CASE
A 67-year-old woman with diabetes, hypertension, and hyperlipidemia presents for evaluation prior to a total hip arthroplasty. She is not taking a β-blocker. Should you prescribe one?

Study summary >>

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting 

β-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials. These trials  have been discredited due to serious methodologic flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³

A new meta-analysis conducted by Bouri et al¹ that excluded the DECREASE trials found that, although preoperative β-blockers reduce the rate of certain nonfatal outcomes, they increase the risk for death and stroke.

STUDY SUMMARY
Preop β-blockers do more harm than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative β-blockers versus placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, two were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed nine high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgic, orthopedic, urologic, and gynecologic surgeries. β-Blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in five trials, bisoprolol in one trial, atenolol in two trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5,264 patients were randomly assigned to receive β-blockers and 5,265 to placebo. There were 162 deaths in the β-blocker group and 129 deaths in the placebo group. Patients who received β-blockers had a 27% increased risk for all-cause mortality (risk ratio [RR] = 1.27). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal MI, nonfatal stroke, and hypotension. β-Blockers lowered the risk for nonfatal MI (RR = 0.73) but increased the risk for nonfatal stroke (RR = 1.73) and hypotension (RR = 1.51).

This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol (100 mg 2 to 4 h before surgery, followed by 200 mg/d for 30 d), in 8,351 patients with, or at risk for, atherosclerotic disease.⁴ While β-blockers reduced the risk for MI and atrial fibrillation, they increased the risk for mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of β-blockers used in this study may have contributed to the excess mortality.

What's new and challenges to implementation >> 

WHAT’S NEW
Avoiding β-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while β-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of β-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate- or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if β-blockers were not used.¹

CAVEATS
Don’t stop β-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking β-blockers. These patients should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION
Reluctance to disregard published guidelines 
Some clinicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIA recommendation (it is reasonable to administer this treatment) for the use of preoperative β-blockade for patients at risk for cardiovascular events who were not previously taking a β-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we await updated recommendations.       

REFERENCES
1. Bouri S, Shun-Shin MJ, Cole GD, et al. Meta-analysis of secure randomised controlled trials of ß-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014;100:456-464.

2. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine; Society for Vascular Surgery; Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. J Am Coll Cardiol. 2009;54:e13-e118.

3. Erasmus Medical Center Follow-up Investigation Committee. Report on the 2012 follow-up investigation of possible breaches of academic integrity (September 30, 2012). CardioBrief. Available at: http://cardiobrief.files.wordpress.com/2012/10/integrity-report-2012-10-english-translation.pdf. Accessed August 14, 2014.

4. Devereaux PJ, Yang H, Yusuf S, et al; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;
371:1839-1847.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(6):E15-E16.

PRACTICE CHANGER

Do not routinely initiate β-blockers in patients undergoing intermediate- or high-risk noncardiac surgery. β-Blockers appear to increase the 30-day risk for all-cause mortality.¹

STRENGTH OF RECOMMENDATION

A: Based on meta-analysis of nine randomized controlled trials (RCTs).¹

ILLUSTRATIVE CASE
A 67-year-old woman with diabetes, hypertension, and hyperlipidemia presents for evaluation prior to a total hip arthroplasty. She is not taking a β-blocker. Should you prescribe one?

Study summary >>

Current guidelines from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend starting 

β-blockers to prevent cardiac events in patients about to undergo intermediate- or high-risk surgery or vascular surgery who have a history of inducible ischemia, coronary artery disease (CAD), or at least one risk factor for CAD.² However, the majority of the evidence for these guidelines, which were published in 2009 and are in the process of being updated, came from the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trials. These trials  have been discredited due to serious methodologic flaws, including falsified descriptions of how outcomes were determined and fictitious databases.³

A new meta-analysis conducted by Bouri et al¹ that excluded the DECREASE trials found that, although preoperative β-blockers reduce the rate of certain nonfatal outcomes, they increase the risk for death and stroke.

STUDY SUMMARY
Preop β-blockers do more harm than good

Bouri et al¹ conducted a meta-analysis of published RCTs evaluating preoperative β-blockers versus placebo for patients undergoing noncardiac surgery. Of the 11 studies that met eligibility criteria, two were the discredited DECREASE trials. Thus, Bouri et al¹ analyzed nine high-quality RCTs that included 10,529 patients.

Most studies included patients undergoing vascular surgery. Some studies also included intra-abdominal, intrathoracic, neurosurgic, orthopedic, urologic, and gynecologic surgeries. β-Blockers were started no more than a day before surgery and were discontinued at hospital discharge or up to 30 days postop. Metoprolol was used in five trials, bisoprolol in one trial, atenolol in two trials, and propranolol in one trial. The primary endpoint was all-cause mortality within 30 days.

A total of 5,264 patients were randomly assigned to receive β-blockers and 5,265 to placebo. There were 162 deaths in the β-blocker group and 129 deaths in the placebo group. Patients who received β-blockers had a 27% increased risk for all-cause mortality (risk ratio [RR] = 1.27). The number needed to harm was 160.

Six of the studies also evaluated rates of nonfatal MI, nonfatal stroke, and hypotension. β-Blockers lowered the risk for nonfatal MI (RR = 0.73) but increased the risk for nonfatal stroke (RR = 1.73) and hypotension (RR = 1.51).

This meta-analysis was dominated by the 2008 Peri-Operative ISchemic Evaluation (POISE) trial, an RCT that compared placebo to extended-release metoprolol (100 mg 2 to 4 h before surgery, followed by 200 mg/d for 30 d), in 8,351 patients with, or at risk for, atherosclerotic disease.⁴ While β-blockers reduced the risk for MI and atrial fibrillation, they increased the risk for mortality and stroke, likely due to drug-induced hypotension. The slightly larger-than-typical doses of β-blockers used in this study may have contributed to the excess mortality.

What's new and challenges to implementation >> 

WHAT’S NEW
Avoiding β-blockers in surgery patients will prevent deaths

Bouri et al¹ found that while β-blockers protect against nonfatal MIs, they increase the risk for nonfatal strokes and death. This new meta-analysis challenges the ACCF/AHA recommendations by suggesting that abandoning the use of β-blockers for preoperative patients who aren’t already taking them will prevent a substantial number of perioperative deaths. Bouri et al¹ estimate that in the United Kingdom, where 47,286 deaths occur annually within 30 days of intermediate- or high-risk procedures, the number of iatrogenic deaths would drop by approximately 10,000 if β-blockers were not used.¹

CAVEATS
Don’t stop β-blockers in patients who already take them

This meta-analysis did not evaluate outcomes in patients who were already taking β-blockers. These patients should continue to take them in the perioperative period, which is in line with current ACCF/AHA guidelines.

CHALLENGES TO IMPLEMENTATION
Reluctance to disregard published guidelines 
Some clinicians may not be comfortable ignoring the current ACCF/AHA guidelines that make a Class IIA recommendation (it is reasonable to administer this treatment) for the use of preoperative β-blockade for patients at risk for cardiovascular events who were not previously taking a β-blocker. This updated meta-analysis excludes the discredited DECREASE trials and challenges us to act against these current guidelines while we await updated recommendations.       

REFERENCES
1. Bouri S, Shun-Shin MJ, Cole GD, et al. Meta-analysis of secure randomised controlled trials of ß-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014;100:456-464.

2. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine; Society for Vascular Surgery; Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. J Am Coll Cardiol. 2009;54:e13-e118.

3. Erasmus Medical Center Follow-up Investigation Committee. Report on the 2012 follow-up investigation of possible breaches of academic integrity (September 30, 2012). CardioBrief. Available at: http://cardiobrief.files.wordpress.com/2012/10/integrity-report-2012-10-english-translation.pdf. Accessed August 14, 2014.

4. Devereaux PJ, Yang H, Yusuf S, et al; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;
371:1839-1847.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(6):E15-E16.

Illustrative case
A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning

Kelleher et al¹ studied neonates born after at least 35 weeks gestation, excluding those who had major congenital anomalies or were non-vigorous (depressed muscle tone or respiration, heart rate <100 beats/min, or both) and born into meconium-stained amniotic fluid, as well as those whom they anticipated would need advanced resuscitation. Neonates were randomly assigned to receive either oronasopharyngeal suctioning with a bulb syringe or wiping of the face and mouth with a towel, starting immediately after the umbilical cord was cut and lasting as long as needed while in the delivery room. The primary outcome was the mean respiratory rate in the first 24 hours after birth. The predefined range of clinical equivalence between the 2 groups was a respiratory rate within 4 breaths/min.

Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects

This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed

This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”
Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURL METHODOLOGY

…..

Illustrative case
A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning

Kelleher et al¹ studied neonates born after at least 35 weeks gestation, excluding those who had major congenital anomalies or were non-vigorous (depressed muscle tone or respiration, heart rate <100 beats/min, or both) and born into meconium-stained amniotic fluid, as well as those whom they anticipated would need advanced resuscitation. Neonates were randomly assigned to receive either oronasopharyngeal suctioning with a bulb syringe or wiping of the face and mouth with a towel, starting immediately after the umbilical cord was cut and lasting as long as needed while in the delivery room. The primary outcome was the mean respiratory rate in the first 24 hours after birth. The predefined range of clinical equivalence between the 2 groups was a respiratory rate within 4 breaths/min.

Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects

This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed

This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”
Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURL METHODOLOGY

…..

Illustrative case
A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning

Kelleher et al¹ studied neonates born after at least 35 weeks gestation, excluding those who had major congenital anomalies or were non-vigorous (depressed muscle tone or respiration, heart rate <100 beats/min, or both) and born into meconium-stained amniotic fluid, as well as those whom they anticipated would need advanced resuscitation. Neonates were randomly assigned to receive either oronasopharyngeal suctioning with a bulb syringe or wiping of the face and mouth with a towel, starting immediately after the umbilical cord was cut and lasting as long as needed while in the delivery room. The primary outcome was the mean respiratory rate in the first 24 hours after birth. The predefined range of clinical equivalence between the 2 groups was a respiratory rate within 4 breaths/min.

Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects

This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed

This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”
Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PURL METHODOLOGY

…..

Illustrative case

A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning


Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

There was no difference in respiratory rates between the suctioning and wiping groups within the first 24 hours of birth. In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects


This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed


This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”

Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning


Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

There was no difference in respiratory rates between the suctioning and wiping groups within the first 24 hours of birth. In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects


This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed


This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”

Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A healthy neonate is born through clear amniotic fluid with no meconium. She is vigorous and has no major congenital anomalies. Does she need oronasopharyngeal suctioning?

No, she does not need suctioning. Although it is still standard practice to perform oronasopharyngeal suctioning with a bulb syringe immediately after delivery, multiple studies have found no benefit to routine suctioning.^2-7 Guidelines from the Neonatal Resuscitation Program (NRP) and other organizations recommend against the practice, even for neonates born through meconium-stained amniotic fluid.^8,9 Suctioning is done because some clinicians believe it reduces the risk of aspiration, especially if there is meconium, and to stimulate breathing, but the evidence suggests that suctioning can stimulate the vagus nerve, which can lead to bradycardia.² Studies that compared babies who did and didn’t receive suctioning found that those who received it had lower Apgar scores and oxygen saturation levels.^2-4

Wiping the neonate’s mouth and nose with a towel is an alternative to suctioning, but until now no trials have compared the outcomes of these 2 methods. Kelleher et al¹ conducted an equivalency trial to determine if wiping the mouth and nose is as effective as oronasopharyngeal suctioning.

STUDY SUMMARY: No difference in breathing 
after wiping or suctioning


Of 506 neonates randomized, 15 were excluded because they were not vigorous and had meconium-stained fluid, and 3 were excluded when their parents withdrew consent. Baseline characteristics for the 2 groups—including maternal age, presence of chronic medical conditions, and body mass index; vaginal vs cesarean delivery; umbilical artery pH; and neonatal sex, ethnic origin, and birth weight—were similar.

There was no difference in respiratory rates between the suctioning and wiping groups within the first 24 hours of birth. In the first 24 hours after birth, the average respiratory rate in the wiping group was 51 breaths/min (standard deviation [SD] ± 8) vs 50 breaths/min (SD ± 6) in the suctioning group. There was no difference in respiratory rates between the 2 groups at 1, 8, or 16 hours after birth. There was also no difference between the 2 groups in Apgar scores or need for advanced resuscitation. More neonates in the wiping group than in the suctioning group were admitted to the neonatal intensive care unit (45 of 246 [18%] vs 30 of 242 [12%]; P=.07), but the study was not powered to assess this outcome.

WHAT'S NEW: Wiping is as effective as suctioning,
 but there are no adverse effects


This study gives us evidence that wiping the face, mouth, and nose is equivalent to suctioning newborns at delivery, and it supports the NRP recommendation against routine suctioning in vigorous neonates born at term. Wiping avoids the potential adverse effects on the respiratory mucosa, bradycardia, and lower Apgar scores associated with suctioning via bulb syringes.

CAVEATS: Wiping is not best 
if a neonate’s airway is obstructed


This study looked only at neonates born after 35 weeks’ gestation who did not have meconium-stained amniotic fluid or congenital abnormalities. Also, NRP guidelines do recommend clearing the airways with a bulb syringe or suction catheter if airway obstruction is evident or positive-pressure ventilation is required.⁸

Another caveat ... In this study,¹ there were 98 treatment crossovers: 64 of the 246 neonates in the wiping group received suctioning, and 34 of the 242 neonates in the suctioning group received wiping. However, this was not likely to change the study’s overall conclusion because a per-treatment analysis also found that wiping and suctioning were equivalent.

CHALLENGES TO IMPLEMENTATION: “We’ve always done it this way”

Practice patterns in a delivery room can be difficult to change. As we work on improving our delivery room environment and changing ingrained habits, the evidence from this study should help support the use of wiping in place of suctioning. The transition from suctioning to wiping also would be facilitated by having easily accessible towels designated for wiping.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.