Clinical Inquiries

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

EVIDENCE SUMMARY

Neither corticosteroids nor platelet-rich plasma are superior to placebo

A 2014 systematic review of RCTs of nonsurgical treatments for lateral epicondylitis identified 4 studies comparing corticosteroid injections to saline or anesthetic injections.¹ In the first study, investigators followed 64 patients for 6 months. Both groups significantly improved from baseline, but there were no differences in pain or function at 1 or 6 months. Skin discoloration occurred in 2 patients who received lidocaine injection and 1 who received dexamethasone.²

In a second RCT of patients with symptoms for > 4 weeks, 39 participants were randomized to either betamethasone/bupivacaine or bupivacaine-only injections. In-person follow-up occurred at 4 and 8 weeks and telephone follow-up at 6 months. Both groups statistically improved from baseline to 6 months. No differences were seen between groups in pain or functional improvement at 4, 8, or 26 weeks, but the betamethasone group showed statistically greater improvement on the Visual Analog Scale (VAS) from 8 weeks to the final 6-month telephone ­follow-up. No functional assessments were reported at 6 months.³

The third RCT of 165 patients with lateral epicondylitis for > 6 weeks evaluated 4 intervention groups: corticosteroid injection with/without physiotherapy and placebo (small-volume saline) injection with/without physiotherapy. At the end of 1 year, the corticosteroid injection groups had less complete recovery (83% vs 96%; relative risk [RR] = 0.86; 99% CI, 0.75-0.99) and more recurrences (54% vs 12%; RR = 0.23; 99% CI, 0.10-0.51) than the placebo groups.⁴

All injections that contained “placebo” significantly improved lateral epicondylitis.

The fourth RCT randomized 120 patients to either 2 mL lidocaine or 1 mL lidocaine plus 1 mL of triamcinolone. At 1-year follow-up, 57 of 60 lidocaine-injected patients had an excellent recovery and 56 of 60 triamcinolone plus lidocaine patients had an excellent recovery.⁵

Platelet-rich plasma. A meta-analysis⁶ of RCTs of PRP vs saline injections included 5 trials and 276 patients with a mean age of 48 years; duration of follow-up was 2 to 12 months. No significant differences were found between the groups for pain score—measured by VAS or the Patient-Rated Tennis Elbow Evaluation (PRTEE)—(standardized mean difference [SMD] = –0.51; 95% CI, –1.32 to –0.30) nor for functional score (SMD = 0.07; 95% CI, –0.46 to 0.33). Two of the trials reported adverse reactions of pain around the injection site: 16% to 20% in the PRP group vs 8% to 15% in the saline group.

Corticosteroids and PRP. A 2013 3-armed RCT⁷ (n = 60) compared 1-time injections of PRP, corticosteroid, and saline for treatment of lateral epicondylitis. Pain was evaluated at 1 and 3 months using the PRTEE. Compared to saline, corticosteroid showed a statistically significant, but not a minimum clinically important, reduction (8% greater improvement) at 1 month but not at 3 months. PRP pain reduction at both 1 and 3 months was not significantly different from placebo. Importantly, a small sample size combined with a high dropout rate (> 70%) limit validity of this study.

Botulinum toxin shows modest pain improvement, but …

A 2017 meta-analysis⁸ of 4 RCTs (n = 278) compared the effectiveness of botulinum toxin vs saline injection and other nonsurgical treatments for lateral epicondylitis. The studies compared the mean differences in pain relief and hand grip strength in adult patients with lateral epicondylitis symptoms for at least 3 months. Compared with saline injection, botulinum toxin injection significantly reduced pain to a small or medium SMD, at 2 to 4 weeks post injection (SMD = –0.73; 95% CI, –1.29 to –0.17); 8 to 12 weeks post injection (SMD = –0.45; 95% CI, –0.74 to –0.15); and 16+ weeks post injection (SMD = –0.54; 95% CI, –0.98 to –0.11). Harm from botulinum toxin was greater than from saline or corticosteroid, with a significant reduction in grip strength at 2 to 4 weeks (SMD = –0.33; 95% CI, –0.59 to –0.08).

Continue to: Prolotherapy needs further study

A 2008 RCT⁹ of 20 adults with at least 6 months of lateral epicondylitis received either prolotherapy (1 part 5% sodium morrhuate, 1.5 parts 50% dextrose, 0.5 parts 4% lidocaine, 0.5 parts 0.5% bupivacaine HCl, and 3.5 parts normal saline) injections or 0.9% saline injections at baseline, 4 weeks, and 8 weeks. On a 10-point Likert scale, the prolotherapy group had a lower mean pain score at 16 weeks than the saline injection group (0.5 vs 3.5), but not at 8 weeks (3.3 vs 3.6). This pilot study’s results are limited by its small sample size.

Hyaluronic acid improves pain, but not enough

A 2010 double-blind RCT¹⁰ (n = 331) compared hyaluronic acid injection vs saline injection in treatment of lateral epicondylitis in adults with > 3 months of symptoms. Two injections were performed 1 week apart, with follow-up at 30 days and at 1 year after the first injection. VAS score in the hyaluronic acid group, at rest and after grip testing, was significantly different (statistically) than in the placebo group but did not meet criteria for minimum clinically important improvement. Review of the literature showed limited follow-up studies on hyaluronic acid for lateral epicondylitis to confirm this RCT.

Autologous blood has no advantage over placebo

The only RCT of autologous blood compared to saline injections¹¹ included patients with lateral epicondylitis for < 6 months: 10 saline injections vs 9 autologous blood injections. Patient scores on the Disabilities of the Arm, Shoulder, and Hand scale (which measures symptoms from 0 to 100; lower is better) showed no difference but favored the saline injections at 2-month (28 vs 20) and 6-month (20 vs 10) follow-up.

Editor’s takeaway

Limiting the evidence review to studies with a placebo comparator clarifies the lack of effectiveness of lateral epicondylitis injections. Neither corticosteroid, platelet-rich plasma, botulinum toxin, prolotherapy, hyaluronic acid, or autologous blood injections have proven superior to saline or anesthetic injections. However, all injections that contained “placebo” significantly improved lateralepicondylitis.

EVIDENCE SUMMARY

Neither corticosteroids nor platelet-rich plasma are superior to placebo

A 2014 systematic review of RCTs of nonsurgical treatments for lateral epicondylitis identified 4 studies comparing corticosteroid injections to saline or anesthetic injections.¹ In the first study, investigators followed 64 patients for 6 months. Both groups significantly improved from baseline, but there were no differences in pain or function at 1 or 6 months. Skin discoloration occurred in 2 patients who received lidocaine injection and 1 who received dexamethasone.²

In a second RCT of patients with symptoms for > 4 weeks, 39 participants were randomized to either betamethasone/bupivacaine or bupivacaine-only injections. In-person follow-up occurred at 4 and 8 weeks and telephone follow-up at 6 months. Both groups statistically improved from baseline to 6 months. No differences were seen between groups in pain or functional improvement at 4, 8, or 26 weeks, but the betamethasone group showed statistically greater improvement on the Visual Analog Scale (VAS) from 8 weeks to the final 6-month telephone ­follow-up. No functional assessments were reported at 6 months.³

The third RCT of 165 patients with lateral epicondylitis for > 6 weeks evaluated 4 intervention groups: corticosteroid injection with/without physiotherapy and placebo (small-volume saline) injection with/without physiotherapy. At the end of 1 year, the corticosteroid injection groups had less complete recovery (83% vs 96%; relative risk [RR] = 0.86; 99% CI, 0.75-0.99) and more recurrences (54% vs 12%; RR = 0.23; 99% CI, 0.10-0.51) than the placebo groups.⁴

All injections that contained “placebo” significantly improved lateral epicondylitis.

The fourth RCT randomized 120 patients to either 2 mL lidocaine or 1 mL lidocaine plus 1 mL of triamcinolone. At 1-year follow-up, 57 of 60 lidocaine-injected patients had an excellent recovery and 56 of 60 triamcinolone plus lidocaine patients had an excellent recovery.⁵

Platelet-rich plasma. A meta-analysis⁶ of RCTs of PRP vs saline injections included 5 trials and 276 patients with a mean age of 48 years; duration of follow-up was 2 to 12 months. No significant differences were found between the groups for pain score—measured by VAS or the Patient-Rated Tennis Elbow Evaluation (PRTEE)—(standardized mean difference [SMD] = –0.51; 95% CI, –1.32 to –0.30) nor for functional score (SMD = 0.07; 95% CI, –0.46 to 0.33). Two of the trials reported adverse reactions of pain around the injection site: 16% to 20% in the PRP group vs 8% to 15% in the saline group.

Corticosteroids and PRP. A 2013 3-armed RCT⁷ (n = 60) compared 1-time injections of PRP, corticosteroid, and saline for treatment of lateral epicondylitis. Pain was evaluated at 1 and 3 months using the PRTEE. Compared to saline, corticosteroid showed a statistically significant, but not a minimum clinically important, reduction (8% greater improvement) at 1 month but not at 3 months. PRP pain reduction at both 1 and 3 months was not significantly different from placebo. Importantly, a small sample size combined with a high dropout rate (> 70%) limit validity of this study.

Botulinum toxin shows modest pain improvement, but …

A 2017 meta-analysis⁸ of 4 RCTs (n = 278) compared the effectiveness of botulinum toxin vs saline injection and other nonsurgical treatments for lateral epicondylitis. The studies compared the mean differences in pain relief and hand grip strength in adult patients with lateral epicondylitis symptoms for at least 3 months. Compared with saline injection, botulinum toxin injection significantly reduced pain to a small or medium SMD, at 2 to 4 weeks post injection (SMD = –0.73; 95% CI, –1.29 to –0.17); 8 to 12 weeks post injection (SMD = –0.45; 95% CI, –0.74 to –0.15); and 16+ weeks post injection (SMD = –0.54; 95% CI, –0.98 to –0.11). Harm from botulinum toxin was greater than from saline or corticosteroid, with a significant reduction in grip strength at 2 to 4 weeks (SMD = –0.33; 95% CI, –0.59 to –0.08).

Continue to: Prolotherapy needs further study

A 2008 RCT⁹ of 20 adults with at least 6 months of lateral epicondylitis received either prolotherapy (1 part 5% sodium morrhuate, 1.5 parts 50% dextrose, 0.5 parts 4% lidocaine, 0.5 parts 0.5% bupivacaine HCl, and 3.5 parts normal saline) injections or 0.9% saline injections at baseline, 4 weeks, and 8 weeks. On a 10-point Likert scale, the prolotherapy group had a lower mean pain score at 16 weeks than the saline injection group (0.5 vs 3.5), but not at 8 weeks (3.3 vs 3.6). This pilot study’s results are limited by its small sample size.

Hyaluronic acid improves pain, but not enough

A 2010 double-blind RCT¹⁰ (n = 331) compared hyaluronic acid injection vs saline injection in treatment of lateral epicondylitis in adults with > 3 months of symptoms. Two injections were performed 1 week apart, with follow-up at 30 days and at 1 year after the first injection. VAS score in the hyaluronic acid group, at rest and after grip testing, was significantly different (statistically) than in the placebo group but did not meet criteria for minimum clinically important improvement. Review of the literature showed limited follow-up studies on hyaluronic acid for lateral epicondylitis to confirm this RCT.

Autologous blood has no advantage over placebo

The only RCT of autologous blood compared to saline injections¹¹ included patients with lateral epicondylitis for < 6 months: 10 saline injections vs 9 autologous blood injections. Patient scores on the Disabilities of the Arm, Shoulder, and Hand scale (which measures symptoms from 0 to 100; lower is better) showed no difference but favored the saline injections at 2-month (28 vs 20) and 6-month (20 vs 10) follow-up.

Editor’s takeaway

Limiting the evidence review to studies with a placebo comparator clarifies the lack of effectiveness of lateral epicondylitis injections. Neither corticosteroid, platelet-rich plasma, botulinum toxin, prolotherapy, hyaluronic acid, or autologous blood injections have proven superior to saline or anesthetic injections. However, all injections that contained “placebo” significantly improved lateralepicondylitis.

EVIDENCE SUMMARY

Neither corticosteroids nor platelet-rich plasma are superior to placebo

A 2014 systematic review of RCTs of nonsurgical treatments for lateral epicondylitis identified 4 studies comparing corticosteroid injections to saline or anesthetic injections.¹ In the first study, investigators followed 64 patients for 6 months. Both groups significantly improved from baseline, but there were no differences in pain or function at 1 or 6 months. Skin discoloration occurred in 2 patients who received lidocaine injection and 1 who received dexamethasone.²

In a second RCT of patients with symptoms for > 4 weeks, 39 participants were randomized to either betamethasone/bupivacaine or bupivacaine-only injections. In-person follow-up occurred at 4 and 8 weeks and telephone follow-up at 6 months. Both groups statistically improved from baseline to 6 months. No differences were seen between groups in pain or functional improvement at 4, 8, or 26 weeks, but the betamethasone group showed statistically greater improvement on the Visual Analog Scale (VAS) from 8 weeks to the final 6-month telephone ­follow-up. No functional assessments were reported at 6 months.³

The third RCT of 165 patients with lateral epicondylitis for > 6 weeks evaluated 4 intervention groups: corticosteroid injection with/without physiotherapy and placebo (small-volume saline) injection with/without physiotherapy. At the end of 1 year, the corticosteroid injection groups had less complete recovery (83% vs 96%; relative risk [RR] = 0.86; 99% CI, 0.75-0.99) and more recurrences (54% vs 12%; RR = 0.23; 99% CI, 0.10-0.51) than the placebo groups.⁴

All injections that contained “placebo” significantly improved lateral epicondylitis.

The fourth RCT randomized 120 patients to either 2 mL lidocaine or 1 mL lidocaine plus 1 mL of triamcinolone. At 1-year follow-up, 57 of 60 lidocaine-injected patients had an excellent recovery and 56 of 60 triamcinolone plus lidocaine patients had an excellent recovery.⁵

Platelet-rich plasma. A meta-analysis⁶ of RCTs of PRP vs saline injections included 5 trials and 276 patients with a mean age of 48 years; duration of follow-up was 2 to 12 months. No significant differences were found between the groups for pain score—measured by VAS or the Patient-Rated Tennis Elbow Evaluation (PRTEE)—(standardized mean difference [SMD] = –0.51; 95% CI, –1.32 to –0.30) nor for functional score (SMD = 0.07; 95% CI, –0.46 to 0.33). Two of the trials reported adverse reactions of pain around the injection site: 16% to 20% in the PRP group vs 8% to 15% in the saline group.

Corticosteroids and PRP. A 2013 3-armed RCT⁷ (n = 60) compared 1-time injections of PRP, corticosteroid, and saline for treatment of lateral epicondylitis. Pain was evaluated at 1 and 3 months using the PRTEE. Compared to saline, corticosteroid showed a statistically significant, but not a minimum clinically important, reduction (8% greater improvement) at 1 month but not at 3 months. PRP pain reduction at both 1 and 3 months was not significantly different from placebo. Importantly, a small sample size combined with a high dropout rate (> 70%) limit validity of this study.

Botulinum toxin shows modest pain improvement, but …

A 2017 meta-analysis⁸ of 4 RCTs (n = 278) compared the effectiveness of botulinum toxin vs saline injection and other nonsurgical treatments for lateral epicondylitis. The studies compared the mean differences in pain relief and hand grip strength in adult patients with lateral epicondylitis symptoms for at least 3 months. Compared with saline injection, botulinum toxin injection significantly reduced pain to a small or medium SMD, at 2 to 4 weeks post injection (SMD = –0.73; 95% CI, –1.29 to –0.17); 8 to 12 weeks post injection (SMD = –0.45; 95% CI, –0.74 to –0.15); and 16+ weeks post injection (SMD = –0.54; 95% CI, –0.98 to –0.11). Harm from botulinum toxin was greater than from saline or corticosteroid, with a significant reduction in grip strength at 2 to 4 weeks (SMD = –0.33; 95% CI, –0.59 to –0.08).

Continue to: Prolotherapy needs further study

A 2008 RCT⁹ of 20 adults with at least 6 months of lateral epicondylitis received either prolotherapy (1 part 5% sodium morrhuate, 1.5 parts 50% dextrose, 0.5 parts 4% lidocaine, 0.5 parts 0.5% bupivacaine HCl, and 3.5 parts normal saline) injections or 0.9% saline injections at baseline, 4 weeks, and 8 weeks. On a 10-point Likert scale, the prolotherapy group had a lower mean pain score at 16 weeks than the saline injection group (0.5 vs 3.5), but not at 8 weeks (3.3 vs 3.6). This pilot study’s results are limited by its small sample size.

Hyaluronic acid improves pain, but not enough

A 2010 double-blind RCT¹⁰ (n = 331) compared hyaluronic acid injection vs saline injection in treatment of lateral epicondylitis in adults with > 3 months of symptoms. Two injections were performed 1 week apart, with follow-up at 30 days and at 1 year after the first injection. VAS score in the hyaluronic acid group, at rest and after grip testing, was significantly different (statistically) than in the placebo group but did not meet criteria for minimum clinically important improvement. Review of the literature showed limited follow-up studies on hyaluronic acid for lateral epicondylitis to confirm this RCT.

Autologous blood has no advantage over placebo

The only RCT of autologous blood compared to saline injections¹¹ included patients with lateral epicondylitis for < 6 months: 10 saline injections vs 9 autologous blood injections. Patient scores on the Disabilities of the Arm, Shoulder, and Hand scale (which measures symptoms from 0 to 100; lower is better) showed no difference but favored the saline injections at 2-month (28 vs 20) and 6-month (20 vs 10) follow-up.

Editor’s takeaway

Limiting the evidence review to studies with a placebo comparator clarifies the lack of effectiveness of lateral epicondylitis injections. Neither corticosteroid, platelet-rich plasma, botulinum toxin, prolotherapy, hyaluronic acid, or autologous blood injections have proven superior to saline or anesthetic injections. However, all injections that contained “placebo” significantly improved lateralepicondylitis.

EVIDENCE SUMMARY

General exercise offers benefit …at least for chronic LBP

A 2017 systematic review of 4 systematic reviews and 50 RCTs (122 total trials) evaluated general exercise vs usual care for acute (< 4 weeks), subacute (4 to 12 weeks), or chronic (≥ 12 weeks) LBP with or without radiculopathy in adults.¹ Exercise was not consistently associated with decreased pain in acute or subacute LBP. For chronic LBP, 3 RCTs (n = 200) associated exercise with decreased pain (weighted mean difference [WMD] = –9.2 on a 0-100 point visual acuity scale; 95% CI, –16.0 to –2.4) and improved function (WMD = –12.4 on the Oswestry Disability Index; 95% CI, –23.0 to –1.7) at short-term follow-up (≤ 3 months). This effect was found to decrease at long-term (≥ 1 year) follow-up (WMD for pain = –4.9; 95% CI, –10.5 to 0.6 and WMD for function = –3.2; 95% CI, 6.0 to –0.4). In a meta-analysis of 10 studies (n = 1992) included in this systematic review, exercise was associated with a lower likelihood of work disability (odds ratio, 0.66; CI, 0.48 to 0.92) at 12 months.¹

Yoga, Pilates, and motor control exercise: Your results may vary

Several reviews have explored the effects of specific exercise modalities on LBP. A 2017 meta-analysis of 9 RCTs in the United States, United Kingdom, and India of nonpregnant adults (≥ 18 years old) with chronic LBP (N = 810) found that yoga (any tradition of yoga with a physical component) vs no exercise demonstrated a statistically, but not clinically, significant decrease in pain at 3 to 4 months (mean difference [MD] = –4.6 on a 0-100 point scale; 95% CI, –7.0 to –2.1), 6 months (MD = –7.8; 95% CI, –13.4 to –2.3), and 12 months (MD = –5.4; 95% CI, –14.5 to –3.7). Clinically significant pain benefit was considered a change of 15 or more points.²

A 2015 meta-analysis of RCTs (10 trials; N = 510) comparing the effects of Pilates (a form of body conditioning involving isometric contractions and core exercises focusing on stability) vs minimal intervention on chronic (> 12 weeks) LBP in nonpregnant adults (≥ 16 years old) found low-quality evidence for decreased pain at short-term follow-up (≤ 3 months; MD = –14.1 on a 0-100 point scale; 95% CI, –18.9 to –9.2). There was moderate-quality evidence for decreased pain at intermediate follow-up (3-12 months; MD = –10.5; 95% CI, –18.5 to –2.6).³

A 2016 systematic review evaluated motor control exercise (MCE; a form of exercise that focuses on trunk muscle control and coordination) in adults (≥ 16 years old) with chronic LBP (≥ 12 weeks). There was low- to moderate-quality evidence that, compared to minimal intervention, MCE decreases pain at short-term (≤ 6 months; 4 RCTs; MD = –10.0 on a 0-100 point scale; 95% CI, –15.7 to –4.4), intermediate (6-12 months; 4 RCTs; MD = –12.6; 95% CI, –20.5 to –4.7), and long-term follow-up (> 12 months; 3 RCTs; MD = –13.0; 95% CI, –18.5 to –7.4). When comparing MCE to general exercise, there were no clinically significant differences in pain or disability at intermediate and long-term follow-up.⁴Common limitations included heterogeneity of intervention methodology, inability to blind results, inability to assess cointerventions, and in some cases, small sample sizes of trials.

Recommendations from others

The 2017 American College of Physicians (ACP) clinical practice guideline on noninvasive treatments for LBP does not recommend exercise therapy in acute or subacute LBP; recommended therapies include superficial heat, massage, acupuncture, or spinal manipulation.⁵ The ACP recommends general exercise, yoga, tai chi, or MCE for chronic LBP, in addition to multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, progressive relaxation, biofeedback, laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.

The 2017 US Department of Veterans Affairs and US Department of Defense clinical practice guideline on treatment of LBP notes insufficient evidence for benefit of clinician-guided exercise therapy in acute LBP.⁶ For chronic LBP, clinician-directed exercise, yoga, tai chi, or Pilates is recommended.

Editor’s takeaway

Convincing evidence demonstrates that exercise modestly improves chronic LBP—but only modestly (4% to 15%), and not in acute LBP. This small magnitude of effect may disappoint expectations, but exercise remains among our better interventions for this common chronic problem. Few—if any—interventions have proven better, and exercise has beneficial side effects, a low cost, and widespread availability.

EVIDENCE SUMMARY

General exercise offers benefit …at least for chronic LBP

A 2017 systematic review of 4 systematic reviews and 50 RCTs (122 total trials) evaluated general exercise vs usual care for acute (< 4 weeks), subacute (4 to 12 weeks), or chronic (≥ 12 weeks) LBP with or without radiculopathy in adults.¹ Exercise was not consistently associated with decreased pain in acute or subacute LBP. For chronic LBP, 3 RCTs (n = 200) associated exercise with decreased pain (weighted mean difference [WMD] = –9.2 on a 0-100 point visual acuity scale; 95% CI, –16.0 to –2.4) and improved function (WMD = –12.4 on the Oswestry Disability Index; 95% CI, –23.0 to –1.7) at short-term follow-up (≤ 3 months). This effect was found to decrease at long-term (≥ 1 year) follow-up (WMD for pain = –4.9; 95% CI, –10.5 to 0.6 and WMD for function = –3.2; 95% CI, 6.0 to –0.4). In a meta-analysis of 10 studies (n = 1992) included in this systematic review, exercise was associated with a lower likelihood of work disability (odds ratio, 0.66; CI, 0.48 to 0.92) at 12 months.¹

Yoga, Pilates, and motor control exercise: Your results may vary

Several reviews have explored the effects of specific exercise modalities on LBP. A 2017 meta-analysis of 9 RCTs in the United States, United Kingdom, and India of nonpregnant adults (≥ 18 years old) with chronic LBP (N = 810) found that yoga (any tradition of yoga with a physical component) vs no exercise demonstrated a statistically, but not clinically, significant decrease in pain at 3 to 4 months (mean difference [MD] = –4.6 on a 0-100 point scale; 95% CI, –7.0 to –2.1), 6 months (MD = –7.8; 95% CI, –13.4 to –2.3), and 12 months (MD = –5.4; 95% CI, –14.5 to –3.7). Clinically significant pain benefit was considered a change of 15 or more points.²

A 2015 meta-analysis of RCTs (10 trials; N = 510) comparing the effects of Pilates (a form of body conditioning involving isometric contractions and core exercises focusing on stability) vs minimal intervention on chronic (> 12 weeks) LBP in nonpregnant adults (≥ 16 years old) found low-quality evidence for decreased pain at short-term follow-up (≤ 3 months; MD = –14.1 on a 0-100 point scale; 95% CI, –18.9 to –9.2). There was moderate-quality evidence for decreased pain at intermediate follow-up (3-12 months; MD = –10.5; 95% CI, –18.5 to –2.6).³

A 2016 systematic review evaluated motor control exercise (MCE; a form of exercise that focuses on trunk muscle control and coordination) in adults (≥ 16 years old) with chronic LBP (≥ 12 weeks). There was low- to moderate-quality evidence that, compared to minimal intervention, MCE decreases pain at short-term (≤ 6 months; 4 RCTs; MD = –10.0 on a 0-100 point scale; 95% CI, –15.7 to –4.4), intermediate (6-12 months; 4 RCTs; MD = –12.6; 95% CI, –20.5 to –4.7), and long-term follow-up (> 12 months; 3 RCTs; MD = –13.0; 95% CI, –18.5 to –7.4). When comparing MCE to general exercise, there were no clinically significant differences in pain or disability at intermediate and long-term follow-up.⁴Common limitations included heterogeneity of intervention methodology, inability to blind results, inability to assess cointerventions, and in some cases, small sample sizes of trials.

Recommendations from others

The 2017 American College of Physicians (ACP) clinical practice guideline on noninvasive treatments for LBP does not recommend exercise therapy in acute or subacute LBP; recommended therapies include superficial heat, massage, acupuncture, or spinal manipulation.⁵ The ACP recommends general exercise, yoga, tai chi, or MCE for chronic LBP, in addition to multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, progressive relaxation, biofeedback, laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.

The 2017 US Department of Veterans Affairs and US Department of Defense clinical practice guideline on treatment of LBP notes insufficient evidence for benefit of clinician-guided exercise therapy in acute LBP.⁶ For chronic LBP, clinician-directed exercise, yoga, tai chi, or Pilates is recommended.

Editor’s takeaway

Convincing evidence demonstrates that exercise modestly improves chronic LBP—but only modestly (4% to 15%), and not in acute LBP. This small magnitude of effect may disappoint expectations, but exercise remains among our better interventions for this common chronic problem. Few—if any—interventions have proven better, and exercise has beneficial side effects, a low cost, and widespread availability.

EVIDENCE SUMMARY

General exercise offers benefit …at least for chronic LBP

A 2017 systematic review of 4 systematic reviews and 50 RCTs (122 total trials) evaluated general exercise vs usual care for acute (< 4 weeks), subacute (4 to 12 weeks), or chronic (≥ 12 weeks) LBP with or without radiculopathy in adults.¹ Exercise was not consistently associated with decreased pain in acute or subacute LBP. For chronic LBP, 3 RCTs (n = 200) associated exercise with decreased pain (weighted mean difference [WMD] = –9.2 on a 0-100 point visual acuity scale; 95% CI, –16.0 to –2.4) and improved function (WMD = –12.4 on the Oswestry Disability Index; 95% CI, –23.0 to –1.7) at short-term follow-up (≤ 3 months). This effect was found to decrease at long-term (≥ 1 year) follow-up (WMD for pain = –4.9; 95% CI, –10.5 to 0.6 and WMD for function = –3.2; 95% CI, 6.0 to –0.4). In a meta-analysis of 10 studies (n = 1992) included in this systematic review, exercise was associated with a lower likelihood of work disability (odds ratio, 0.66; CI, 0.48 to 0.92) at 12 months.¹

Yoga, Pilates, and motor control exercise: Your results may vary

Several reviews have explored the effects of specific exercise modalities on LBP. A 2017 meta-analysis of 9 RCTs in the United States, United Kingdom, and India of nonpregnant adults (≥ 18 years old) with chronic LBP (N = 810) found that yoga (any tradition of yoga with a physical component) vs no exercise demonstrated a statistically, but not clinically, significant decrease in pain at 3 to 4 months (mean difference [MD] = –4.6 on a 0-100 point scale; 95% CI, –7.0 to –2.1), 6 months (MD = –7.8; 95% CI, –13.4 to –2.3), and 12 months (MD = –5.4; 95% CI, –14.5 to –3.7). Clinically significant pain benefit was considered a change of 15 or more points.²

A 2015 meta-analysis of RCTs (10 trials; N = 510) comparing the effects of Pilates (a form of body conditioning involving isometric contractions and core exercises focusing on stability) vs minimal intervention on chronic (> 12 weeks) LBP in nonpregnant adults (≥ 16 years old) found low-quality evidence for decreased pain at short-term follow-up (≤ 3 months; MD = –14.1 on a 0-100 point scale; 95% CI, –18.9 to –9.2). There was moderate-quality evidence for decreased pain at intermediate follow-up (3-12 months; MD = –10.5; 95% CI, –18.5 to –2.6).³

A 2016 systematic review evaluated motor control exercise (MCE; a form of exercise that focuses on trunk muscle control and coordination) in adults (≥ 16 years old) with chronic LBP (≥ 12 weeks). There was low- to moderate-quality evidence that, compared to minimal intervention, MCE decreases pain at short-term (≤ 6 months; 4 RCTs; MD = –10.0 on a 0-100 point scale; 95% CI, –15.7 to –4.4), intermediate (6-12 months; 4 RCTs; MD = –12.6; 95% CI, –20.5 to –4.7), and long-term follow-up (> 12 months; 3 RCTs; MD = –13.0; 95% CI, –18.5 to –7.4). When comparing MCE to general exercise, there were no clinically significant differences in pain or disability at intermediate and long-term follow-up.⁴Common limitations included heterogeneity of intervention methodology, inability to blind results, inability to assess cointerventions, and in some cases, small sample sizes of trials.

Recommendations from others

The 2017 American College of Physicians (ACP) clinical practice guideline on noninvasive treatments for LBP does not recommend exercise therapy in acute or subacute LBP; recommended therapies include superficial heat, massage, acupuncture, or spinal manipulation.⁵ The ACP recommends general exercise, yoga, tai chi, or MCE for chronic LBP, in addition to multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, progressive relaxation, biofeedback, laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.

The 2017 US Department of Veterans Affairs and US Department of Defense clinical practice guideline on treatment of LBP notes insufficient evidence for benefit of clinician-guided exercise therapy in acute LBP.⁶ For chronic LBP, clinician-directed exercise, yoga, tai chi, or Pilates is recommended.

Editor’s takeaway

Convincing evidence demonstrates that exercise modestly improves chronic LBP—but only modestly (4% to 15%), and not in acute LBP. This small magnitude of effect may disappoint expectations, but exercise remains among our better interventions for this common chronic problem. Few—if any—interventions have proven better, and exercise has beneficial side effects, a low cost, and widespread availability.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.