Clinical Inquiries

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, better known as statins (atorvastatin, fluvastatin, lovastatin, rosuvastatin, pravastatin, simvastatin), have been shown to lower LDL cholesterol in the primary and secondary prevention of cardiovascular disease. Although often effective as monotherapy, combination regimens may be needed to reach LDL cholesterol goals.^1-4 Ezetimibe, niacin, and bile acid sequestrants (cholestyramine [Questran], colesevelam [WelChol], colestipol [Colestid]) have complementary effects that suggest they may be appropriate for use in combination with a statin.

Adding a bile acid sequestrant to statin monotherapy does not appear to increase the risk of systemic toxicity.⁵ A systematic review found that adding colestipol or cholestyramine to a statin provides an additional 7% to 20% absolute LDL cholesterol reduction.¹ A randomized placebo-controlled trial demonstrated that combination therapy with colesevelam has similar effects. The absolute LDL cholesterol reduction of with atorvastatin (Lipitor) alone (10 mg daily) increased from 38% to 48% after adding colesevelam 3.8 g daily (10% absolute LDL cholesterol reduction).⁶

Statin/ezetimibe combination therapy is FDA-approved, and provides an additional 12% to 21% absolute LDL cholesterol reduction.² Although considered safe, adding ezetimibe increases the incidence of elevated hepatic transaminases from 0.4% to 1.3%.⁷ A double-blind trial randomized 769 patients on statin monotherapy who were above their NCEP LDL goal to either placebo or ezetimibe 10 mg daily.³ Absolute LDL cholesterol reductions were 25.1% with ezetimibe vs 3.7% with placebo, and LDL goal attainment was 71.5% with ezetimibe vs 18.9% with placebo (secondary endpoint). In one retrospective analysis, ezetimibe provided a 19% absolute LDL cholesterol reduction when added to a bile acid sequestrant.⁸

Combinations of statins with fibrates (fenofibrate [Tricor], gemfibrozil [Lopid]) can treat combined dyslipidemia by decreasing LDL cholesterol more than 40%, decreasing triglycerides over 50%, and raising high-density lipoprotein (HDL) cholesterol more than 20%.⁹ Prospective controlled trials have shown regression of atherosclerotic lesions with this combination, but have also shown increased risks of myopathy.^6,10 In an analysis of 36 controlled clinical trials (1674 patients) that evaluated statin-fibrate combinations, 0.12% of patients developed myopathy, but none developed rhabdomyolysis or kidney failure.¹⁰ Experts believe myopathy risk is greater with gemfibrozil than fenofibrate, based on gemfibrozil’s inhibition of statin glucuronidation, and case reports in the literature.⁵ Accordingly, the maximum approved daily doses of lovastatin (Mevacor), simvastatin (Zocor), and rosuvastatin (Crestor) are lowered (20, 10, and 10 mg, respectively) when used with gemfibrozil.

Adding niacin to statin monotherapy can modify combined dyslipidemia as does a statin/fibrate combination, by lowering LDL cholesterol and triglycerides, and raising HDL cholesterol to an even greater extent. Patients are more intolerant to a statin/niacin combination (eg, flushing) than to a statin/fibrate combination, but have a lower risk of myopathy with the former.⁵ The combination of statin/niacin may be more desirable than statin/fibrate for patients with more severe mixed dyslipidemia, especially those with very low HDL cholesterol values, when monotherapy regimens are not completely effective. A fixed combination of lovastatin with extended-release niacin (Advicor) is commercially available.^4,11

TABLE
Commonly used combination therapies with estimated changes in lipid values

Recommendations from others

The NCEP Adult Treatment Panel III recommends adding a bile acid sequestrant, niacin, or ezetimibe to a statin when additional LDL cholesterol-lowering is needed to reach NCEP-III goals, and adding niacin or a fibrate to a statin to lower non-HDL cholesterol for patients with persistently high triglycerides or low HDL cholesterol.^12,13

The American Association of Clinical Endocrinologists also recommends using these combinations for the following circumstances: severe dyslipidemia, inadequate response to monotherapy, dose-dependent adverse effects, and certain mixed dyslipidemias.¹⁴ However, the clinical advisory on statins by American Heart Association/American College of Cardiology/National Heart, Lung and Blood Institute warns that statin/fibrate combinations (especially with gemfibrozil) or statin/niacin (although rare) are risk factors for statin-associated myopathy.⁵

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, better known as statins (atorvastatin, fluvastatin, lovastatin, rosuvastatin, pravastatin, simvastatin), have been shown to lower LDL cholesterol in the primary and secondary prevention of cardiovascular disease. Although often effective as monotherapy, combination regimens may be needed to reach LDL cholesterol goals.^1-4 Ezetimibe, niacin, and bile acid sequestrants (cholestyramine [Questran], colesevelam [WelChol], colestipol [Colestid]) have complementary effects that suggest they may be appropriate for use in combination with a statin.

Adding a bile acid sequestrant to statin monotherapy does not appear to increase the risk of systemic toxicity.⁵ A systematic review found that adding colestipol or cholestyramine to a statin provides an additional 7% to 20% absolute LDL cholesterol reduction.¹ A randomized placebo-controlled trial demonstrated that combination therapy with colesevelam has similar effects. The absolute LDL cholesterol reduction of with atorvastatin (Lipitor) alone (10 mg daily) increased from 38% to 48% after adding colesevelam 3.8 g daily (10% absolute LDL cholesterol reduction).⁶

Statin/ezetimibe combination therapy is FDA-approved, and provides an additional 12% to 21% absolute LDL cholesterol reduction.² Although considered safe, adding ezetimibe increases the incidence of elevated hepatic transaminases from 0.4% to 1.3%.⁷ A double-blind trial randomized 769 patients on statin monotherapy who were above their NCEP LDL goal to either placebo or ezetimibe 10 mg daily.³ Absolute LDL cholesterol reductions were 25.1% with ezetimibe vs 3.7% with placebo, and LDL goal attainment was 71.5% with ezetimibe vs 18.9% with placebo (secondary endpoint). In one retrospective analysis, ezetimibe provided a 19% absolute LDL cholesterol reduction when added to a bile acid sequestrant.⁸

Combinations of statins with fibrates (fenofibrate [Tricor], gemfibrozil [Lopid]) can treat combined dyslipidemia by decreasing LDL cholesterol more than 40%, decreasing triglycerides over 50%, and raising high-density lipoprotein (HDL) cholesterol more than 20%.⁹ Prospective controlled trials have shown regression of atherosclerotic lesions with this combination, but have also shown increased risks of myopathy.^6,10 In an analysis of 36 controlled clinical trials (1674 patients) that evaluated statin-fibrate combinations, 0.12% of patients developed myopathy, but none developed rhabdomyolysis or kidney failure.¹⁰ Experts believe myopathy risk is greater with gemfibrozil than fenofibrate, based on gemfibrozil’s inhibition of statin glucuronidation, and case reports in the literature.⁵ Accordingly, the maximum approved daily doses of lovastatin (Mevacor), simvastatin (Zocor), and rosuvastatin (Crestor) are lowered (20, 10, and 10 mg, respectively) when used with gemfibrozil.

Adding niacin to statin monotherapy can modify combined dyslipidemia as does a statin/fibrate combination, by lowering LDL cholesterol and triglycerides, and raising HDL cholesterol to an even greater extent. Patients are more intolerant to a statin/niacin combination (eg, flushing) than to a statin/fibrate combination, but have a lower risk of myopathy with the former.⁵ The combination of statin/niacin may be more desirable than statin/fibrate for patients with more severe mixed dyslipidemia, especially those with very low HDL cholesterol values, when monotherapy regimens are not completely effective. A fixed combination of lovastatin with extended-release niacin (Advicor) is commercially available.^4,11

TABLE
Commonly used combination therapies with estimated changes in lipid values

Recommendations from others

The NCEP Adult Treatment Panel III recommends adding a bile acid sequestrant, niacin, or ezetimibe to a statin when additional LDL cholesterol-lowering is needed to reach NCEP-III goals, and adding niacin or a fibrate to a statin to lower non-HDL cholesterol for patients with persistently high triglycerides or low HDL cholesterol.^12,13

The American Association of Clinical Endocrinologists also recommends using these combinations for the following circumstances: severe dyslipidemia, inadequate response to monotherapy, dose-dependent adverse effects, and certain mixed dyslipidemias.¹⁴ However, the clinical advisory on statins by American Heart Association/American College of Cardiology/National Heart, Lung and Blood Institute warns that statin/fibrate combinations (especially with gemfibrozil) or statin/niacin (although rare) are risk factors for statin-associated myopathy.⁵

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, better known as statins (atorvastatin, fluvastatin, lovastatin, rosuvastatin, pravastatin, simvastatin), have been shown to lower LDL cholesterol in the primary and secondary prevention of cardiovascular disease. Although often effective as monotherapy, combination regimens may be needed to reach LDL cholesterol goals.^1-4 Ezetimibe, niacin, and bile acid sequestrants (cholestyramine [Questran], colesevelam [WelChol], colestipol [Colestid]) have complementary effects that suggest they may be appropriate for use in combination with a statin.

Adding a bile acid sequestrant to statin monotherapy does not appear to increase the risk of systemic toxicity.⁵ A systematic review found that adding colestipol or cholestyramine to a statin provides an additional 7% to 20% absolute LDL cholesterol reduction.¹ A randomized placebo-controlled trial demonstrated that combination therapy with colesevelam has similar effects. The absolute LDL cholesterol reduction of with atorvastatin (Lipitor) alone (10 mg daily) increased from 38% to 48% after adding colesevelam 3.8 g daily (10% absolute LDL cholesterol reduction).⁶

Statin/ezetimibe combination therapy is FDA-approved, and provides an additional 12% to 21% absolute LDL cholesterol reduction.² Although considered safe, adding ezetimibe increases the incidence of elevated hepatic transaminases from 0.4% to 1.3%.⁷ A double-blind trial randomized 769 patients on statin monotherapy who were above their NCEP LDL goal to either placebo or ezetimibe 10 mg daily.³ Absolute LDL cholesterol reductions were 25.1% with ezetimibe vs 3.7% with placebo, and LDL goal attainment was 71.5% with ezetimibe vs 18.9% with placebo (secondary endpoint). In one retrospective analysis, ezetimibe provided a 19% absolute LDL cholesterol reduction when added to a bile acid sequestrant.⁸

Combinations of statins with fibrates (fenofibrate [Tricor], gemfibrozil [Lopid]) can treat combined dyslipidemia by decreasing LDL cholesterol more than 40%, decreasing triglycerides over 50%, and raising high-density lipoprotein (HDL) cholesterol more than 20%.⁹ Prospective controlled trials have shown regression of atherosclerotic lesions with this combination, but have also shown increased risks of myopathy.^6,10 In an analysis of 36 controlled clinical trials (1674 patients) that evaluated statin-fibrate combinations, 0.12% of patients developed myopathy, but none developed rhabdomyolysis or kidney failure.¹⁰ Experts believe myopathy risk is greater with gemfibrozil than fenofibrate, based on gemfibrozil’s inhibition of statin glucuronidation, and case reports in the literature.⁵ Accordingly, the maximum approved daily doses of lovastatin (Mevacor), simvastatin (Zocor), and rosuvastatin (Crestor) are lowered (20, 10, and 10 mg, respectively) when used with gemfibrozil.

Adding niacin to statin monotherapy can modify combined dyslipidemia as does a statin/fibrate combination, by lowering LDL cholesterol and triglycerides, and raising HDL cholesterol to an even greater extent. Patients are more intolerant to a statin/niacin combination (eg, flushing) than to a statin/fibrate combination, but have a lower risk of myopathy with the former.⁵ The combination of statin/niacin may be more desirable than statin/fibrate for patients with more severe mixed dyslipidemia, especially those with very low HDL cholesterol values, when monotherapy regimens are not completely effective. A fixed combination of lovastatin with extended-release niacin (Advicor) is commercially available.^4,11

TABLE
Commonly used combination therapies with estimated changes in lipid values

Recommendations from others

The NCEP Adult Treatment Panel III recommends adding a bile acid sequestrant, niacin, or ezetimibe to a statin when additional LDL cholesterol-lowering is needed to reach NCEP-III goals, and adding niacin or a fibrate to a statin to lower non-HDL cholesterol for patients with persistently high triglycerides or low HDL cholesterol.^12,13

The American Association of Clinical Endocrinologists also recommends using these combinations for the following circumstances: severe dyslipidemia, inadequate response to monotherapy, dose-dependent adverse effects, and certain mixed dyslipidemias.¹⁴ However, the clinical advisory on statins by American Heart Association/American College of Cardiology/National Heart, Lung and Blood Institute warns that statin/fibrate combinations (especially with gemfibrozil) or statin/niacin (although rare) are risk factors for statin-associated myopathy.⁵

Evidence summary

Bronchiolitis is the most common diagnosis among hospitalized infants aged <1 year in the US.¹ It is usually mild with a self-limited course. A 1997 study following 1113 healthy full-term infants through 20 consecutive winter seasons showed a 5% hospitalization rate of all infants with a positive respiratory syncytial virus (RSV) cult\ure (hospitalization rates with other pathogens were not reported), confirming the mild nature of most cases of bronchiolitis.² RSV accounts for 50% to 80% of bronchiolitis, along with other pathogens such as parainfluenza virus, influenza virus, and human metapneumovirus. A recent analysis of Centers for Disease Control and Prevention data from 1979 to 1997 showed that an average of 95 children died annually in the US from bronchiolitis, and 77% of these were aged <1 year (median age at death was 3 months).³

When discrete measures such as vital signs and scoring scales for respiratory distress are compared, infants who have mild disease courses are very similar to those who subsequently have a more severe illness. This, combined with the low incidence of serious illness, lowers the predictive value of any single clinical criteria for hospital admission (including oxygen saturation, respiratory rate, apparent respiratory distress, and day of illness) to the degree that no objective criteria are useful to make a decision for or against hospitalization.^4,5

In 2 good-quality retrospective case-control studies, which enrolled infants with milder disease discharged from emergency departments, no infants returned with illness severe enough to require admission to an intensive care unit (ICU).^5,6 No criteria were found that could predict subsequent severe course and need for admission.

One good-quality prospective study that enrolled 213 infants, younger than 13 months and presenting with bronchiolitis as outpatients found that physician impression of appearance was a better predictor of severe illness than numeric scoring systems such as the Yale Observation Scale or the Clinical Asthma Score.⁷ Pulse oximetry (<95%), prematurity (<34 weeks gestational age), respiratory rate >70/minute, atelectasis, “ill” or “toxic” appearance, and age <3 months were associated with more severe illness (defined as inability to remain alert and active or well hydrated throughout their illness). Oxygen saturation (SaO₂) <95% was the most objective predictor of severity (positive predictive value=87%; negative predictive value=73%). The study population was more ill than what is typical in outpatient settings (42% required admission and 11% required mechanical ventilation); therefore the positive predictive value would be lower in a milder, more typical outpatient population.

In a retrospective case-control study of 542 otherwise healthy full-term infants aged <1 year admitted for bronchiolitis with positive RSV tests, tachypnea (rate >80) and hypoxia (SaO₂<85%) were predictive of the need for pediatric ICU–level care (the specificity for predicting deterioration was 97%, but the sensitivity was only 30%).⁴ The authors concluded that the use of any specific variable for a single patient is limited because of its low sensitivity for detecting the risk of an adverse outcome.

Several studies have attempted to define admission criteria or decision-making tools for admission of these infants, but all used the clinical opinion of the attending pediatrician as their gold standard and many excluded infants discharged within 24 hours, thus limiting their applicability to an outpatient population.^4,7-10 Common criteria in these studies were an SaO₂ ≤93% or history of complicating illness such as congenital heart disease, prematurity, or lung disease, plus the clinical impression of the attending physician.

TABLE
Risk factors for deterioration in infants with bronchiolitis

Recommendations from others

The American Academy of Pediatrics does not have a guideline addressing this issue. The only guideline listed at the National Guidelines Clearinghouse was a 2005 Cincinnati Children’s Hospital Medical Center guideline for managing infants with bronchiolitis; it is grounded in assuring good patient oxygenation and hydration.¹¹ This guideline does not give specific criteria for admission but leaves this decision to the judgment of the physician. It also notes that the benefits of hospitalization center on the ability to closely monitor clinical status (including airway maintenance and hydration) and educating parents. The guideline recommends starting supplemental oxygen when SaO₂ is consistently less than 91% and weaning when higher than 94%.

Evidence summary

Bronchiolitis is the most common diagnosis among hospitalized infants aged <1 year in the US.¹ It is usually mild with a self-limited course. A 1997 study following 1113 healthy full-term infants through 20 consecutive winter seasons showed a 5% hospitalization rate of all infants with a positive respiratory syncytial virus (RSV) cult\ure (hospitalization rates with other pathogens were not reported), confirming the mild nature of most cases of bronchiolitis.² RSV accounts for 50% to 80% of bronchiolitis, along with other pathogens such as parainfluenza virus, influenza virus, and human metapneumovirus. A recent analysis of Centers for Disease Control and Prevention data from 1979 to 1997 showed that an average of 95 children died annually in the US from bronchiolitis, and 77% of these were aged <1 year (median age at death was 3 months).³

When discrete measures such as vital signs and scoring scales for respiratory distress are compared, infants who have mild disease courses are very similar to those who subsequently have a more severe illness. This, combined with the low incidence of serious illness, lowers the predictive value of any single clinical criteria for hospital admission (including oxygen saturation, respiratory rate, apparent respiratory distress, and day of illness) to the degree that no objective criteria are useful to make a decision for or against hospitalization.^4,5

In 2 good-quality retrospective case-control studies, which enrolled infants with milder disease discharged from emergency departments, no infants returned with illness severe enough to require admission to an intensive care unit (ICU).^5,6 No criteria were found that could predict subsequent severe course and need for admission.

One good-quality prospective study that enrolled 213 infants, younger than 13 months and presenting with bronchiolitis as outpatients found that physician impression of appearance was a better predictor of severe illness than numeric scoring systems such as the Yale Observation Scale or the Clinical Asthma Score.⁷ Pulse oximetry (<95%), prematurity (<34 weeks gestational age), respiratory rate >70/minute, atelectasis, “ill” or “toxic” appearance, and age <3 months were associated with more severe illness (defined as inability to remain alert and active or well hydrated throughout their illness). Oxygen saturation (SaO₂) <95% was the most objective predictor of severity (positive predictive value=87%; negative predictive value=73%). The study population was more ill than what is typical in outpatient settings (42% required admission and 11% required mechanical ventilation); therefore the positive predictive value would be lower in a milder, more typical outpatient population.

In a retrospective case-control study of 542 otherwise healthy full-term infants aged <1 year admitted for bronchiolitis with positive RSV tests, tachypnea (rate >80) and hypoxia (SaO₂<85%) were predictive of the need for pediatric ICU–level care (the specificity for predicting deterioration was 97%, but the sensitivity was only 30%).⁴ The authors concluded that the use of any specific variable for a single patient is limited because of its low sensitivity for detecting the risk of an adverse outcome.

Several studies have attempted to define admission criteria or decision-making tools for admission of these infants, but all used the clinical opinion of the attending pediatrician as their gold standard and many excluded infants discharged within 24 hours, thus limiting their applicability to an outpatient population.^4,7-10 Common criteria in these studies were an SaO₂ ≤93% or history of complicating illness such as congenital heart disease, prematurity, or lung disease, plus the clinical impression of the attending physician.

TABLE
Risk factors for deterioration in infants with bronchiolitis

Recommendations from others

The American Academy of Pediatrics does not have a guideline addressing this issue. The only guideline listed at the National Guidelines Clearinghouse was a 2005 Cincinnati Children’s Hospital Medical Center guideline for managing infants with bronchiolitis; it is grounded in assuring good patient oxygenation and hydration.¹¹ This guideline does not give specific criteria for admission but leaves this decision to the judgment of the physician. It also notes that the benefits of hospitalization center on the ability to closely monitor clinical status (including airway maintenance and hydration) and educating parents. The guideline recommends starting supplemental oxygen when SaO₂ is consistently less than 91% and weaning when higher than 94%.

Evidence summary

Bronchiolitis is the most common diagnosis among hospitalized infants aged <1 year in the US.¹ It is usually mild with a self-limited course. A 1997 study following 1113 healthy full-term infants through 20 consecutive winter seasons showed a 5% hospitalization rate of all infants with a positive respiratory syncytial virus (RSV) cult\ure (hospitalization rates with other pathogens were not reported), confirming the mild nature of most cases of bronchiolitis.² RSV accounts for 50% to 80% of bronchiolitis, along with other pathogens such as parainfluenza virus, influenza virus, and human metapneumovirus. A recent analysis of Centers for Disease Control and Prevention data from 1979 to 1997 showed that an average of 95 children died annually in the US from bronchiolitis, and 77% of these were aged <1 year (median age at death was 3 months).³

When discrete measures such as vital signs and scoring scales for respiratory distress are compared, infants who have mild disease courses are very similar to those who subsequently have a more severe illness. This, combined with the low incidence of serious illness, lowers the predictive value of any single clinical criteria for hospital admission (including oxygen saturation, respiratory rate, apparent respiratory distress, and day of illness) to the degree that no objective criteria are useful to make a decision for or against hospitalization.^4,5

In 2 good-quality retrospective case-control studies, which enrolled infants with milder disease discharged from emergency departments, no infants returned with illness severe enough to require admission to an intensive care unit (ICU).^5,6 No criteria were found that could predict subsequent severe course and need for admission.

One good-quality prospective study that enrolled 213 infants, younger than 13 months and presenting with bronchiolitis as outpatients found that physician impression of appearance was a better predictor of severe illness than numeric scoring systems such as the Yale Observation Scale or the Clinical Asthma Score.⁷ Pulse oximetry (<95%), prematurity (<34 weeks gestational age), respiratory rate >70/minute, atelectasis, “ill” or “toxic” appearance, and age <3 months were associated with more severe illness (defined as inability to remain alert and active or well hydrated throughout their illness). Oxygen saturation (SaO₂) <95% was the most objective predictor of severity (positive predictive value=87%; negative predictive value=73%). The study population was more ill than what is typical in outpatient settings (42% required admission and 11% required mechanical ventilation); therefore the positive predictive value would be lower in a milder, more typical outpatient population.

In a retrospective case-control study of 542 otherwise healthy full-term infants aged <1 year admitted for bronchiolitis with positive RSV tests, tachypnea (rate >80) and hypoxia (SaO₂<85%) were predictive of the need for pediatric ICU–level care (the specificity for predicting deterioration was 97%, but the sensitivity was only 30%).⁴ The authors concluded that the use of any specific variable for a single patient is limited because of its low sensitivity for detecting the risk of an adverse outcome.

Several studies have attempted to define admission criteria or decision-making tools for admission of these infants, but all used the clinical opinion of the attending pediatrician as their gold standard and many excluded infants discharged within 24 hours, thus limiting their applicability to an outpatient population.^4,7-10 Common criteria in these studies were an SaO₂ ≤93% or history of complicating illness such as congenital heart disease, prematurity, or lung disease, plus the clinical impression of the attending physician.

TABLE
Risk factors for deterioration in infants with bronchiolitis

Recommendations from others

The American Academy of Pediatrics does not have a guideline addressing this issue. The only guideline listed at the National Guidelines Clearinghouse was a 2005 Cincinnati Children’s Hospital Medical Center guideline for managing infants with bronchiolitis; it is grounded in assuring good patient oxygenation and hydration.¹¹ This guideline does not give specific criteria for admission but leaves this decision to the judgment of the physician. It also notes that the benefits of hospitalization center on the ability to closely monitor clinical status (including airway maintenance and hydration) and educating parents. The guideline recommends starting supplemental oxygen when SaO₂ is consistently less than 91% and weaning when higher than 94%.

Evidence summary

Contrary to what many physicians learned from their mentors—and to what many patients believe—no food or food additive has been proven to cause migraine headaches; and in fact, good evidence disproves this notion. The primary foods once thought to trigger migraines were cheese, alcohol, chocolate and citrus fruit.¹ Conversely, it appears that regular supplementation with some nutrients reduces the frequency and intensity of migraines (TABLE 1).

Vasoactive amines. Vasoactive amines (ie, tyramine and phenylethylamine) are present in aged cheese and red wine. One randomized trial of 80 patients with frequent migraines showed that tyramine and placebo induced migraine at the same rate.² A systematic review on the relation of vasoactive amines to migraine found no evidence that any biogenic amines in red wine, cheese, or chocolate cause migraine.³ Furthermore, an uncontrolled prospective trial failed to show that amount or type of alcohol correlates with migraines, but it did find a correlation between stressful events and migraines. These stressful events also correlated with a higher alcohol intake.⁴ One final small randomized controlled trial enrolling children found no difference in migraine frequency between high fiber/high vasoactive amine and a high fiber/low vasoactive amine diet.⁵ In contrast to these RCTs, one series of lower-evidence-level patient surveys from a tertiary clinic reported that approximately 12% to 28% of patients perceived migraines were triggered by various foods (ie, cheese, wine, beer, chocolate).⁶

Chocolate. The role of chocolate in instigating headache was investigated in a 63-subject double-blind RCT comparing chocolate with carob. Chocolate was not more likely to provoke headache than carob in any of the headache diagnostic groups (P=.83). These results were independent of subjects’ beliefs regarding the role of chocolate in the instigation of headache (P=.39). Unfortunately, this trial included multiple headache types, with only 50% being migraine.⁷

Omega-3 fatty acids. A small double-blind crossover study of 27 adolescents over 5 months showed no difference between fish oil supplementation and “placebo supplementation” with olive oil. The dose of fish oil used is approximately equivalent to 1.5 g of the recently approved Omacor fish oil capsules. Interestingly, the subjects reported dramatic decreases in headache frequency (15 per month down to 2 episodes per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point Likert scale) with both compounds.⁸ The possibility of olive oil being an active comparator muddles interpretation of the results.

Riboflavin. A good-quality RCT compared riboflavin 400 mg/d with placebo for prophylaxis of migraines.⁹ Using intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (P=.005) and headache days (P=.012). The proportion of patients who improved by at least 50% was 15% for placebo and 59% for riboflavin (P=.002). The number needed to treat (NNT) was 2.3. Adverse events were very rare—1 case of diarrhea was reported causing withdrawal (number needed to harm [NNH]=33.3). The effect of riboflavin on migraine began at 1 month but was maximal at 3 months, when this study ended. The most pronounced effect was shorter migraine attacks followed by fewer migraine attacks. An additional large case series found that high-dose riboflavin reduced headache days by 50% (P<.05) and use of abortive medicines by 36% (P<.05).¹⁰

Magnesium. A good-quality RCT of 81 adults given 600 mg of magnesium or placebo showed that by weeks 9 to 12 frequency of attacks was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared with the baseline (P<.05; NNT=3.9). However, diarrhea was reported among 18.6% of magnesium recipients (NNH=5.2).¹¹ Additionally, a very small randomized trial of 20 women found that magnesium 360 mg/d in the luteal phase reduced the number of days with menstrual-related migraines (P<.03) when compared with placebo. However, the absolute magnitude of the difference was not reported, so it is unclear if this study is clinically useful or can be extended to all patients with migraines.¹²

Low-fat diet. A prospective cohort trial of 54 patients evaluated the effect of lowering total fat intake per day. The dietary intervention successfully lowered fat intake from 65.9 to 27.8 g/d and was associated with statistically significant decreases in headache frequency (median decrease from 6 to 1 per week), intensity (median decrease 2.9 to 0.5 on a scale from 0 to 5), duration, and medication intake (P<.0001 for all measures, confidence interval not available).¹³

Caffeine. One case series found that adolescents and children ingesting over 1400 mg/wk of caffeine from cola drinks experienced resolution of headaches with gradual reduction in cola intake,¹⁴ but no prospective trials to confirm this observation have been completed. It is important to note that reduction in migraines may have been due to reduction in other ingredients, not just caffeine.

Riboflavin/magnesium/feverfew. One double-blind RCT compared a compound with daily doses of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with the proposed placebo of riboflavin 25 mg. There was no difference in response between the compound and the riboflavin placebo; however, response to riboflavin 25 mg was higher than expected for a placebo (44%). Further study with a placebo free of active ingredients is required to determine the ultimate effectiveness of this compound.¹⁵

TABLE
Effects of dietary compounds on migraine headaches

Recommendations from others

The American Academy of Neurology makes no mention of dietary therapy in its most recent guideline on migraine, but it does identify both riboflavin (fair evidence) and magnesium (weak evidence) as safe options for preventing migraine.¹⁶ The National Headache Foundation makes no statement regarding dietary therapy for migraines, but it does identify riboflavin and magnesium as possible preventive therapies.¹⁷

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Contrary to what many physicians learned from their mentors—and to what many patients believe—no food or food additive has been proven to cause migraine headaches; and in fact, good evidence disproves this notion. The primary foods once thought to trigger migraines were cheese, alcohol, chocolate and citrus fruit.¹ Conversely, it appears that regular supplementation with some nutrients reduces the frequency and intensity of migraines (TABLE 1).

Vasoactive amines. Vasoactive amines (ie, tyramine and phenylethylamine) are present in aged cheese and red wine. One randomized trial of 80 patients with frequent migraines showed that tyramine and placebo induced migraine at the same rate.² A systematic review on the relation of vasoactive amines to migraine found no evidence that any biogenic amines in red wine, cheese, or chocolate cause migraine.³ Furthermore, an uncontrolled prospective trial failed to show that amount or type of alcohol correlates with migraines, but it did find a correlation between stressful events and migraines. These stressful events also correlated with a higher alcohol intake.⁴ One final small randomized controlled trial enrolling children found no difference in migraine frequency between high fiber/high vasoactive amine and a high fiber/low vasoactive amine diet.⁵ In contrast to these RCTs, one series of lower-evidence-level patient surveys from a tertiary clinic reported that approximately 12% to 28% of patients perceived migraines were triggered by various foods (ie, cheese, wine, beer, chocolate).⁶

Chocolate. The role of chocolate in instigating headache was investigated in a 63-subject double-blind RCT comparing chocolate with carob. Chocolate was not more likely to provoke headache than carob in any of the headache diagnostic groups (P=.83). These results were independent of subjects’ beliefs regarding the role of chocolate in the instigation of headache (P=.39). Unfortunately, this trial included multiple headache types, with only 50% being migraine.⁷

Omega-3 fatty acids. A small double-blind crossover study of 27 adolescents over 5 months showed no difference between fish oil supplementation and “placebo supplementation” with olive oil. The dose of fish oil used is approximately equivalent to 1.5 g of the recently approved Omacor fish oil capsules. Interestingly, the subjects reported dramatic decreases in headache frequency (15 per month down to 2 episodes per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point Likert scale) with both compounds.⁸ The possibility of olive oil being an active comparator muddles interpretation of the results.

Riboflavin. A good-quality RCT compared riboflavin 400 mg/d with placebo for prophylaxis of migraines.⁹ Using intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (P=.005) and headache days (P=.012). The proportion of patients who improved by at least 50% was 15% for placebo and 59% for riboflavin (P=.002). The number needed to treat (NNT) was 2.3. Adverse events were very rare—1 case of diarrhea was reported causing withdrawal (number needed to harm [NNH]=33.3). The effect of riboflavin on migraine began at 1 month but was maximal at 3 months, when this study ended. The most pronounced effect was shorter migraine attacks followed by fewer migraine attacks. An additional large case series found that high-dose riboflavin reduced headache days by 50% (P<.05) and use of abortive medicines by 36% (P<.05).¹⁰

Magnesium. A good-quality RCT of 81 adults given 600 mg of magnesium or placebo showed that by weeks 9 to 12 frequency of attacks was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared with the baseline (P<.05; NNT=3.9). However, diarrhea was reported among 18.6% of magnesium recipients (NNH=5.2).¹¹ Additionally, a very small randomized trial of 20 women found that magnesium 360 mg/d in the luteal phase reduced the number of days with menstrual-related migraines (P<.03) when compared with placebo. However, the absolute magnitude of the difference was not reported, so it is unclear if this study is clinically useful or can be extended to all patients with migraines.¹²

Low-fat diet. A prospective cohort trial of 54 patients evaluated the effect of lowering total fat intake per day. The dietary intervention successfully lowered fat intake from 65.9 to 27.8 g/d and was associated with statistically significant decreases in headache frequency (median decrease from 6 to 1 per week), intensity (median decrease 2.9 to 0.5 on a scale from 0 to 5), duration, and medication intake (P<.0001 for all measures, confidence interval not available).¹³

Caffeine. One case series found that adolescents and children ingesting over 1400 mg/wk of caffeine from cola drinks experienced resolution of headaches with gradual reduction in cola intake,¹⁴ but no prospective trials to confirm this observation have been completed. It is important to note that reduction in migraines may have been due to reduction in other ingredients, not just caffeine.

Riboflavin/magnesium/feverfew. One double-blind RCT compared a compound with daily doses of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with the proposed placebo of riboflavin 25 mg. There was no difference in response between the compound and the riboflavin placebo; however, response to riboflavin 25 mg was higher than expected for a placebo (44%). Further study with a placebo free of active ingredients is required to determine the ultimate effectiveness of this compound.¹⁵

TABLE
Effects of dietary compounds on migraine headaches

Recommendations from others

The American Academy of Neurology makes no mention of dietary therapy in its most recent guideline on migraine, but it does identify both riboflavin (fair evidence) and magnesium (weak evidence) as safe options for preventing migraine.¹⁶ The National Headache Foundation makes no statement regarding dietary therapy for migraines, but it does identify riboflavin and magnesium as possible preventive therapies.¹⁷

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Contrary to what many physicians learned from their mentors—and to what many patients believe—no food or food additive has been proven to cause migraine headaches; and in fact, good evidence disproves this notion. The primary foods once thought to trigger migraines were cheese, alcohol, chocolate and citrus fruit.¹ Conversely, it appears that regular supplementation with some nutrients reduces the frequency and intensity of migraines (TABLE 1).

Vasoactive amines. Vasoactive amines (ie, tyramine and phenylethylamine) are present in aged cheese and red wine. One randomized trial of 80 patients with frequent migraines showed that tyramine and placebo induced migraine at the same rate.² A systematic review on the relation of vasoactive amines to migraine found no evidence that any biogenic amines in red wine, cheese, or chocolate cause migraine.³ Furthermore, an uncontrolled prospective trial failed to show that amount or type of alcohol correlates with migraines, but it did find a correlation between stressful events and migraines. These stressful events also correlated with a higher alcohol intake.⁴ One final small randomized controlled trial enrolling children found no difference in migraine frequency between high fiber/high vasoactive amine and a high fiber/low vasoactive amine diet.⁵ In contrast to these RCTs, one series of lower-evidence-level patient surveys from a tertiary clinic reported that approximately 12% to 28% of patients perceived migraines were triggered by various foods (ie, cheese, wine, beer, chocolate).⁶

Chocolate. The role of chocolate in instigating headache was investigated in a 63-subject double-blind RCT comparing chocolate with carob. Chocolate was not more likely to provoke headache than carob in any of the headache diagnostic groups (P=.83). These results were independent of subjects’ beliefs regarding the role of chocolate in the instigation of headache (P=.39). Unfortunately, this trial included multiple headache types, with only 50% being migraine.⁷

Omega-3 fatty acids. A small double-blind crossover study of 27 adolescents over 5 months showed no difference between fish oil supplementation and “placebo supplementation” with olive oil. The dose of fish oil used is approximately equivalent to 1.5 g of the recently approved Omacor fish oil capsules. Interestingly, the subjects reported dramatic decreases in headache frequency (15 per month down to 2 episodes per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point Likert scale) with both compounds.⁸ The possibility of olive oil being an active comparator muddles interpretation of the results.

Riboflavin. A good-quality RCT compared riboflavin 400 mg/d with placebo for prophylaxis of migraines.⁹ Using intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (P=.005) and headache days (P=.012). The proportion of patients who improved by at least 50% was 15% for placebo and 59% for riboflavin (P=.002). The number needed to treat (NNT) was 2.3. Adverse events were very rare—1 case of diarrhea was reported causing withdrawal (number needed to harm [NNH]=33.3). The effect of riboflavin on migraine began at 1 month but was maximal at 3 months, when this study ended. The most pronounced effect was shorter migraine attacks followed by fewer migraine attacks. An additional large case series found that high-dose riboflavin reduced headache days by 50% (P<.05) and use of abortive medicines by 36% (P<.05).¹⁰

Magnesium. A good-quality RCT of 81 adults given 600 mg of magnesium or placebo showed that by weeks 9 to 12 frequency of attacks was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared with the baseline (P<.05; NNT=3.9). However, diarrhea was reported among 18.6% of magnesium recipients (NNH=5.2).¹¹ Additionally, a very small randomized trial of 20 women found that magnesium 360 mg/d in the luteal phase reduced the number of days with menstrual-related migraines (P<.03) when compared with placebo. However, the absolute magnitude of the difference was not reported, so it is unclear if this study is clinically useful or can be extended to all patients with migraines.¹²

Low-fat diet. A prospective cohort trial of 54 patients evaluated the effect of lowering total fat intake per day. The dietary intervention successfully lowered fat intake from 65.9 to 27.8 g/d and was associated with statistically significant decreases in headache frequency (median decrease from 6 to 1 per week), intensity (median decrease 2.9 to 0.5 on a scale from 0 to 5), duration, and medication intake (P<.0001 for all measures, confidence interval not available).¹³

Caffeine. One case series found that adolescents and children ingesting over 1400 mg/wk of caffeine from cola drinks experienced resolution of headaches with gradual reduction in cola intake,¹⁴ but no prospective trials to confirm this observation have been completed. It is important to note that reduction in migraines may have been due to reduction in other ingredients, not just caffeine.

Riboflavin/magnesium/feverfew. One double-blind RCT compared a compound with daily doses of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with the proposed placebo of riboflavin 25 mg. There was no difference in response between the compound and the riboflavin placebo; however, response to riboflavin 25 mg was higher than expected for a placebo (44%). Further study with a placebo free of active ingredients is required to determine the ultimate effectiveness of this compound.¹⁵

TABLE
Effects of dietary compounds on migraine headaches

Recommendations from others

The American Academy of Neurology makes no mention of dietary therapy in its most recent guideline on migraine, but it does identify both riboflavin (fair evidence) and magnesium (weak evidence) as safe options for preventing migraine.¹⁶ The National Headache Foundation makes no statement regarding dietary therapy for migraines, but it does identify riboflavin and magnesium as possible preventive therapies.¹⁷

Acknowledgments

The opinions and assertions contained herein are the private views of the author and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

In a systematic review of 23 studies involving 56,304 patients, the prevalence of ICA varied by the number of family members affected; 2.3% in general population, 4% for 1 primary family member affected, and 8% for 2 or more primary family members affected.¹ The annual rate of rupture in a retrospective study of 1449 patients was 0.5%.² Rate of rupture varied based on size of aneurysm, location, and gender. In a more recent case series of relatives of people who suffered an subarachnoid hemorrhage, the absolute lifetime risk of subarachnoid hemorrhage was 4.7% (95% confidence interval [CI], 3.1–6.3%).²

In a case series of 626 patients having 1 primary relative with ICA, screening with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) backup resulted in 0.9 months increased life expectancy per person screened, at the cost of 19 years of decreased function.³ A mathematical model applied to this study showed that surgery improved life expectancy by an average of 2.5 years; a 6-month postoperative functional assessment found functional impairment in 11 of 18 surgical patients (number needed to harm [NNH]=1.6). In a separate study using data from the same population, being a sibling of an ICA sufferer increased risk of ICA (relative risk=3.8, though with a wide 95% CI of 1.1–29.3).⁴ Neither hypertension nor hypercholesterolemia conferred increased risk of ICA, and the risk conferred by smoking and use of alcohol was statistically insignificant.⁴

In a study of MRA with digital subtraction angiography backup, conducted using theoretical models, screening individuals having 2 or more first-degree relatives with aneurysm would result in severe morbidity or death in 26 individuals per 1000 patients screened, vs 15 per 1000 unscreened individuals over a 30-year period.⁵ These results were achieved assuming an ICA prevalence estimate of 9.8%, as determined from an earlier population study of individuals with at least 2 first-degree relatives with ICA. The lower ICA prevalence rate of 4% for patients with only 1 primary affected relative would yield an even more favorable result for not screening.

A mathematical model for evaluating cost effectiveness of screening for asymptomatic intracranial aneurysms in the general population determined there is a quality-adjusted life-year reduction for presumed ICA prevalence rates as high as 10%, given an annual rate of rupture of 0.05%.⁶ The average cost was $1121 for those who underwent screening vs $147 for those who did not. The presumed variables of prevalence, annual rates of ICA rupture, and surgical mortality and morbidity greatly influenced cost-effectiveness. Screening could be reasonable in populations with higher rupture rates, and if surgical morbidity and mortality decline.

Recently, the psychosocial aspects of screening for ICA have been studied. In 1 case series of 105 patients, 35 screen-positive patients scored lower for quality of life than 70 screen-negative patients. However, only 3 patients regretted participating in screening.⁷ An observational study of 980 first-degree relatives of patients with subarachnoid hemorrhage determined that offering screening for ICA did not provoke anxiety or depression.⁸ Providing thorough counseling before screening can help to alleviate the patient’s anxiety.

Recommendations from others

In 2000, the Stroke Council of the American Heart Association concluded that screening is not efficacious in populations having a single first-degree relative with aneurismal subarachnoid hemorrhage or intracranial aneurysm.⁹

Evidence summary

In a systematic review of 23 studies involving 56,304 patients, the prevalence of ICA varied by the number of family members affected; 2.3% in general population, 4% for 1 primary family member affected, and 8% for 2 or more primary family members affected.¹ The annual rate of rupture in a retrospective study of 1449 patients was 0.5%.² Rate of rupture varied based on size of aneurysm, location, and gender. In a more recent case series of relatives of people who suffered an subarachnoid hemorrhage, the absolute lifetime risk of subarachnoid hemorrhage was 4.7% (95% confidence interval [CI], 3.1–6.3%).²

In a case series of 626 patients having 1 primary relative with ICA, screening with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) backup resulted in 0.9 months increased life expectancy per person screened, at the cost of 19 years of decreased function.³ A mathematical model applied to this study showed that surgery improved life expectancy by an average of 2.5 years; a 6-month postoperative functional assessment found functional impairment in 11 of 18 surgical patients (number needed to harm [NNH]=1.6). In a separate study using data from the same population, being a sibling of an ICA sufferer increased risk of ICA (relative risk=3.8, though with a wide 95% CI of 1.1–29.3).⁴ Neither hypertension nor hypercholesterolemia conferred increased risk of ICA, and the risk conferred by smoking and use of alcohol was statistically insignificant.⁴

In a study of MRA with digital subtraction angiography backup, conducted using theoretical models, screening individuals having 2 or more first-degree relatives with aneurysm would result in severe morbidity or death in 26 individuals per 1000 patients screened, vs 15 per 1000 unscreened individuals over a 30-year period.⁵ These results were achieved assuming an ICA prevalence estimate of 9.8%, as determined from an earlier population study of individuals with at least 2 first-degree relatives with ICA. The lower ICA prevalence rate of 4% for patients with only 1 primary affected relative would yield an even more favorable result for not screening.

A mathematical model for evaluating cost effectiveness of screening for asymptomatic intracranial aneurysms in the general population determined there is a quality-adjusted life-year reduction for presumed ICA prevalence rates as high as 10%, given an annual rate of rupture of 0.05%.⁶ The average cost was $1121 for those who underwent screening vs $147 for those who did not. The presumed variables of prevalence, annual rates of ICA rupture, and surgical mortality and morbidity greatly influenced cost-effectiveness. Screening could be reasonable in populations with higher rupture rates, and if surgical morbidity and mortality decline.

Recently, the psychosocial aspects of screening for ICA have been studied. In 1 case series of 105 patients, 35 screen-positive patients scored lower for quality of life than 70 screen-negative patients. However, only 3 patients regretted participating in screening.⁷ An observational study of 980 first-degree relatives of patients with subarachnoid hemorrhage determined that offering screening for ICA did not provoke anxiety or depression.⁸ Providing thorough counseling before screening can help to alleviate the patient’s anxiety.

Recommendations from others

In 2000, the Stroke Council of the American Heart Association concluded that screening is not efficacious in populations having a single first-degree relative with aneurismal subarachnoid hemorrhage or intracranial aneurysm.⁹

Evidence summary

In a systematic review of 23 studies involving 56,304 patients, the prevalence of ICA varied by the number of family members affected; 2.3% in general population, 4% for 1 primary family member affected, and 8% for 2 or more primary family members affected.¹ The annual rate of rupture in a retrospective study of 1449 patients was 0.5%.² Rate of rupture varied based on size of aneurysm, location, and gender. In a more recent case series of relatives of people who suffered an subarachnoid hemorrhage, the absolute lifetime risk of subarachnoid hemorrhage was 4.7% (95% confidence interval [CI], 3.1–6.3%).²

In a case series of 626 patients having 1 primary relative with ICA, screening with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) backup resulted in 0.9 months increased life expectancy per person screened, at the cost of 19 years of decreased function.³ A mathematical model applied to this study showed that surgery improved life expectancy by an average of 2.5 years; a 6-month postoperative functional assessment found functional impairment in 11 of 18 surgical patients (number needed to harm [NNH]=1.6). In a separate study using data from the same population, being a sibling of an ICA sufferer increased risk of ICA (relative risk=3.8, though with a wide 95% CI of 1.1–29.3).⁴ Neither hypertension nor hypercholesterolemia conferred increased risk of ICA, and the risk conferred by smoking and use of alcohol was statistically insignificant.⁴

In a study of MRA with digital subtraction angiography backup, conducted using theoretical models, screening individuals having 2 or more first-degree relatives with aneurysm would result in severe morbidity or death in 26 individuals per 1000 patients screened, vs 15 per 1000 unscreened individuals over a 30-year period.⁵ These results were achieved assuming an ICA prevalence estimate of 9.8%, as determined from an earlier population study of individuals with at least 2 first-degree relatives with ICA. The lower ICA prevalence rate of 4% for patients with only 1 primary affected relative would yield an even more favorable result for not screening.

A mathematical model for evaluating cost effectiveness of screening for asymptomatic intracranial aneurysms in the general population determined there is a quality-adjusted life-year reduction for presumed ICA prevalence rates as high as 10%, given an annual rate of rupture of 0.05%.⁶ The average cost was $1121 for those who underwent screening vs $147 for those who did not. The presumed variables of prevalence, annual rates of ICA rupture, and surgical mortality and morbidity greatly influenced cost-effectiveness. Screening could be reasonable in populations with higher rupture rates, and if surgical morbidity and mortality decline.

Recently, the psychosocial aspects of screening for ICA have been studied. In 1 case series of 105 patients, 35 screen-positive patients scored lower for quality of life than 70 screen-negative patients. However, only 3 patients regretted participating in screening.⁷ An observational study of 980 first-degree relatives of patients with subarachnoid hemorrhage determined that offering screening for ICA did not provoke anxiety or depression.⁸ Providing thorough counseling before screening can help to alleviate the patient’s anxiety.

Recommendations from others

In 2000, the Stroke Council of the American Heart Association concluded that screening is not efficacious in populations having a single first-degree relative with aneurismal subarachnoid hemorrhage or intracranial aneurysm.⁹

Evidence summary

A 2005 Cochrane review of 11 RCTs and 1 quasi-randomized trial, with a total of 1720 adults and children, investigated several antibiotics for treatment and prophylaxis of pertussis. The outcome measures used to assess the efficacy of antibiotic treatment or prophylaxis vary between the trials and most of them did not report the immunization status of the participants. The Cochrane review included 1 meta-analysis of 3 studies with 252 participants, comparing azithromycin for 3 days, erythromycin estolate for 7 days, and clarithromycin for 7 days (short-term treatment) with erythromycin estolate for fourteen days (long-term treatment). The study showed equal efficacy in eradication of B pertussis from the nasopharynx of 99.2% to 97.7% (absolute risk reduction [ARR]=1.44%; 95% confidence interval [CI], –1.58 to 4.46). There were fewer side effects with the short-term treatment (32.1% vs 48.9%; ARR=16%; 95% CI, 7.84 to 25.84).¹

A large, multicenter RCT of 477 children of 6 months to 16 years of age demonstrated that a 5-day treatment with azithromycin eradicated B pertussis from the nasopharynx as effectively as a 10-day course of erythromycin estolate.² Similarly, trimethoprim/sulfamethoxazole proved as effective as erythromycin in eliminating B pertussis from the nasopharynx.

Although tetracycline and chloramphenicol are effective treatments for pertussis, they are not recommended because of their side effects.¹ Six randomized trials failed to show any statistically significant difference between antibiotics and placebo on frequency and severity of cough or duration of pertussis disease.¹ A randomized, placebo-controlled trial studied 300 household contacts of children with culture-positive pertussis. There was no statistically significant difference in either the frequency of pertussis disease or rate of positive cultures in household contacts between the erythromycin group (2.1%) and the placebo group (5.1%) (ARR=2.95%; 95% CI, –1.21 to 7.11).¹

Another Cochrane review of 8 trials examined the effectiveness of the symptomatic treatment of cough in children and adults with pertussis. There were many problems with the methodological quality of these trials, including small sample sizes and poor reporting of the methods. Diphenhydramine, pertussis immunoglobulin, corticosteroids and salbutamol were compared with placebo. There were no statistically significant differences in coughing paroxysms, mean number of whoops per 24 hours or in duration of hospital stay between these interventions and placebo.³

Extracorporeal circulatory life support has been used to maintain perfusion for patients with severe disease. The mortality of these patients is very high.⁴ No RCTs of the effectiveness of this intervention has been performed.

TABLE
Antibiotics for treatment and prophylaxis of pertussis in children and adults

Recommendations from others

The Centers for Disease Control and Prevention recommends erythromycin for 14 days as a first choice for the treatment and prophylaxis of pertussis. Antibiotics should be started no later than 3 weeks after the onset of cough. Trimethoprim-sulfamethoxazole can be used as an alternative treatment for patients who do not tolerate erythromycin. Prophylaxis is recommended for all household and close contacts if pertussis is highly suspected.⁵

The American Academy of Pediatrics recommends the use of azithromycin and clarithromycin as an alternative treatment for patients who do not tolerate erythromycin. ⁵

A national consensus conference on pertussis held in Canada recommended prophylaxis for household contacts of an infant aged <1 year, pregnant women during the third trimester, and for vulnerable individuals who have had face-to-face exposure, or have shared confined air for >1 hour.⁶

Evidence summary

A 2005 Cochrane review of 11 RCTs and 1 quasi-randomized trial, with a total of 1720 adults and children, investigated several antibiotics for treatment and prophylaxis of pertussis. The outcome measures used to assess the efficacy of antibiotic treatment or prophylaxis vary between the trials and most of them did not report the immunization status of the participants. The Cochrane review included 1 meta-analysis of 3 studies with 252 participants, comparing azithromycin for 3 days, erythromycin estolate for 7 days, and clarithromycin for 7 days (short-term treatment) with erythromycin estolate for fourteen days (long-term treatment). The study showed equal efficacy in eradication of B pertussis from the nasopharynx of 99.2% to 97.7% (absolute risk reduction [ARR]=1.44%; 95% confidence interval [CI], –1.58 to 4.46). There were fewer side effects with the short-term treatment (32.1% vs 48.9%; ARR=16%; 95% CI, 7.84 to 25.84).¹

A large, multicenter RCT of 477 children of 6 months to 16 years of age demonstrated that a 5-day treatment with azithromycin eradicated B pertussis from the nasopharynx as effectively as a 10-day course of erythromycin estolate.² Similarly, trimethoprim/sulfamethoxazole proved as effective as erythromycin in eliminating B pertussis from the nasopharynx.

Although tetracycline and chloramphenicol are effective treatments for pertussis, they are not recommended because of their side effects.¹ Six randomized trials failed to show any statistically significant difference between antibiotics and placebo on frequency and severity of cough or duration of pertussis disease.¹ A randomized, placebo-controlled trial studied 300 household contacts of children with culture-positive pertussis. There was no statistically significant difference in either the frequency of pertussis disease or rate of positive cultures in household contacts between the erythromycin group (2.1%) and the placebo group (5.1%) (ARR=2.95%; 95% CI, –1.21 to 7.11).¹

Another Cochrane review of 8 trials examined the effectiveness of the symptomatic treatment of cough in children and adults with pertussis. There were many problems with the methodological quality of these trials, including small sample sizes and poor reporting of the methods. Diphenhydramine, pertussis immunoglobulin, corticosteroids and salbutamol were compared with placebo. There were no statistically significant differences in coughing paroxysms, mean number of whoops per 24 hours or in duration of hospital stay between these interventions and placebo.³

Extracorporeal circulatory life support has been used to maintain perfusion for patients with severe disease. The mortality of these patients is very high.⁴ No RCTs of the effectiveness of this intervention has been performed.

TABLE
Antibiotics for treatment and prophylaxis of pertussis in children and adults

Recommendations from others

The Centers for Disease Control and Prevention recommends erythromycin for 14 days as a first choice for the treatment and prophylaxis of pertussis. Antibiotics should be started no later than 3 weeks after the onset of cough. Trimethoprim-sulfamethoxazole can be used as an alternative treatment for patients who do not tolerate erythromycin. Prophylaxis is recommended for all household and close contacts if pertussis is highly suspected.⁵

The American Academy of Pediatrics recommends the use of azithromycin and clarithromycin as an alternative treatment for patients who do not tolerate erythromycin. ⁵

A national consensus conference on pertussis held in Canada recommended prophylaxis for household contacts of an infant aged <1 year, pregnant women during the third trimester, and for vulnerable individuals who have had face-to-face exposure, or have shared confined air for >1 hour.⁶

Evidence summary

A 2005 Cochrane review of 11 RCTs and 1 quasi-randomized trial, with a total of 1720 adults and children, investigated several antibiotics for treatment and prophylaxis of pertussis. The outcome measures used to assess the efficacy of antibiotic treatment or prophylaxis vary between the trials and most of them did not report the immunization status of the participants. The Cochrane review included 1 meta-analysis of 3 studies with 252 participants, comparing azithromycin for 3 days, erythromycin estolate for 7 days, and clarithromycin for 7 days (short-term treatment) with erythromycin estolate for fourteen days (long-term treatment). The study showed equal efficacy in eradication of B pertussis from the nasopharynx of 99.2% to 97.7% (absolute risk reduction [ARR]=1.44%; 95% confidence interval [CI], –1.58 to 4.46). There were fewer side effects with the short-term treatment (32.1% vs 48.9%; ARR=16%; 95% CI, 7.84 to 25.84).¹

A large, multicenter RCT of 477 children of 6 months to 16 years of age demonstrated that a 5-day treatment with azithromycin eradicated B pertussis from the nasopharynx as effectively as a 10-day course of erythromycin estolate.² Similarly, trimethoprim/sulfamethoxazole proved as effective as erythromycin in eliminating B pertussis from the nasopharynx.

Although tetracycline and chloramphenicol are effective treatments for pertussis, they are not recommended because of their side effects.¹ Six randomized trials failed to show any statistically significant difference between antibiotics and placebo on frequency and severity of cough or duration of pertussis disease.¹ A randomized, placebo-controlled trial studied 300 household contacts of children with culture-positive pertussis. There was no statistically significant difference in either the frequency of pertussis disease or rate of positive cultures in household contacts between the erythromycin group (2.1%) and the placebo group (5.1%) (ARR=2.95%; 95% CI, –1.21 to 7.11).¹

Another Cochrane review of 8 trials examined the effectiveness of the symptomatic treatment of cough in children and adults with pertussis. There were many problems with the methodological quality of these trials, including small sample sizes and poor reporting of the methods. Diphenhydramine, pertussis immunoglobulin, corticosteroids and salbutamol were compared with placebo. There were no statistically significant differences in coughing paroxysms, mean number of whoops per 24 hours or in duration of hospital stay between these interventions and placebo.³

Extracorporeal circulatory life support has been used to maintain perfusion for patients with severe disease. The mortality of these patients is very high.⁴ No RCTs of the effectiveness of this intervention has been performed.

TABLE
Antibiotics for treatment and prophylaxis of pertussis in children and adults

Recommendations from others

The Centers for Disease Control and Prevention recommends erythromycin for 14 days as a first choice for the treatment and prophylaxis of pertussis. Antibiotics should be started no later than 3 weeks after the onset of cough. Trimethoprim-sulfamethoxazole can be used as an alternative treatment for patients who do not tolerate erythromycin. Prophylaxis is recommended for all household and close contacts if pertussis is highly suspected.⁵

The American Academy of Pediatrics recommends the use of azithromycin and clarithromycin as an alternative treatment for patients who do not tolerate erythromycin. ⁵

A national consensus conference on pertussis held in Canada recommended prophylaxis for household contacts of an infant aged <1 year, pregnant women during the third trimester, and for vulnerable individuals who have had face-to-face exposure, or have shared confined air for >1 hour.⁶

Evidence summary

Evidence supporting the effectiveness of TCAs is strong, especially amitriptyline, in fibromyalgia-related symptoms. A metaanalysis that included 10 trials of low-dose TCAs (eg, 25–50 mg of amitriptyline) showed moderate improvement in sleep, pain, fatigue, and overall well-being (number needed to treat [NNT] for improvement=4).¹ A meta-analysis of 5 RCTs on cyclobenzaprine, a muscle relaxant chemically related to TCAs, demonstrated its effect in improving pain and sleep disturbance (NNT=5).²

There is less evidence that other medications are effective. Two of 3 RCTs of fluoxetine (Prozac) have shown that it was more effective than placebo, and 2 RCTs have shown that fluoxetine and sertraline (Zoloft) are comparable to amitriptyline.³ Single RCTs conducted on duloxetine and milnacipran, new SNRIs, demonstrated them to be more effective than placebo in improving pain and scores on the Fibromyalgia Impact Questionnaire (FIQ).³ Three RCTs have shown that tramadol (with or without acetaminophen) is more effective than placebo in improving pain, number of tender points and FIQ score.³

A single RCT has demonstrated that pregabalin (Lyrica), a new anticonvulsant, reduces pain more than placebo.³

Among nonpharmacological interventions, aerobic exercise and cognitive behavioral therapy have the strongest evidence of effectiveness. A systematic review assessing various exercise programs on symptoms of fibromyalgia showed that aerobic exercise produces short-term improvements in cardiovascular fitness, tender-point pressure pain threshold, and patient- and physicianrated global well-being. Three of these trials included long-term follow-up of the exercise group participants. Patients who continued exercising maintained their improved physical functioning.⁴

Cognitive behavioral therapy has been shown to reduce symptoms in 5 RCTs.3 Combining cognitive behavioral therapy with education and exercise has also been effective in 5 additional RCTs.³ Some evidence suggests that acupuncture, massage, warm baths, and biofeedback are effective, but this is limited because of methodological issues in the studies that have been conducted to date.³

Recommendations from others

A recently published evidence-based guideline sponsored by the American Pain Society recommends low-dose TCAs, cyclobenzaprine, cardiovascular exercise, and cognitive behavioral therapy alone or with exercise as first-line therapy along with patient education and treatment of comorbid conditions. For patients that do not improve, it recommends a trial of an SSRI, an SNRI, tramadol, an anticonvulsant, combination medications, or referral.³

Evidence summary

Evidence supporting the effectiveness of TCAs is strong, especially amitriptyline, in fibromyalgia-related symptoms. A metaanalysis that included 10 trials of low-dose TCAs (eg, 25–50 mg of amitriptyline) showed moderate improvement in sleep, pain, fatigue, and overall well-being (number needed to treat [NNT] for improvement=4).¹ A meta-analysis of 5 RCTs on cyclobenzaprine, a muscle relaxant chemically related to TCAs, demonstrated its effect in improving pain and sleep disturbance (NNT=5).²

There is less evidence that other medications are effective. Two of 3 RCTs of fluoxetine (Prozac) have shown that it was more effective than placebo, and 2 RCTs have shown that fluoxetine and sertraline (Zoloft) are comparable to amitriptyline.³ Single RCTs conducted on duloxetine and milnacipran, new SNRIs, demonstrated them to be more effective than placebo in improving pain and scores on the Fibromyalgia Impact Questionnaire (FIQ).³ Three RCTs have shown that tramadol (with or without acetaminophen) is more effective than placebo in improving pain, number of tender points and FIQ score.³

A single RCT has demonstrated that pregabalin (Lyrica), a new anticonvulsant, reduces pain more than placebo.³

Among nonpharmacological interventions, aerobic exercise and cognitive behavioral therapy have the strongest evidence of effectiveness. A systematic review assessing various exercise programs on symptoms of fibromyalgia showed that aerobic exercise produces short-term improvements in cardiovascular fitness, tender-point pressure pain threshold, and patient- and physicianrated global well-being. Three of these trials included long-term follow-up of the exercise group participants. Patients who continued exercising maintained their improved physical functioning.⁴

Cognitive behavioral therapy has been shown to reduce symptoms in 5 RCTs.3 Combining cognitive behavioral therapy with education and exercise has also been effective in 5 additional RCTs.³ Some evidence suggests that acupuncture, massage, warm baths, and biofeedback are effective, but this is limited because of methodological issues in the studies that have been conducted to date.³

Recommendations from others

A recently published evidence-based guideline sponsored by the American Pain Society recommends low-dose TCAs, cyclobenzaprine, cardiovascular exercise, and cognitive behavioral therapy alone or with exercise as first-line therapy along with patient education and treatment of comorbid conditions. For patients that do not improve, it recommends a trial of an SSRI, an SNRI, tramadol, an anticonvulsant, combination medications, or referral.³

Evidence summary

Evidence supporting the effectiveness of TCAs is strong, especially amitriptyline, in fibromyalgia-related symptoms. A metaanalysis that included 10 trials of low-dose TCAs (eg, 25–50 mg of amitriptyline) showed moderate improvement in sleep, pain, fatigue, and overall well-being (number needed to treat [NNT] for improvement=4).¹ A meta-analysis of 5 RCTs on cyclobenzaprine, a muscle relaxant chemically related to TCAs, demonstrated its effect in improving pain and sleep disturbance (NNT=5).²

There is less evidence that other medications are effective. Two of 3 RCTs of fluoxetine (Prozac) have shown that it was more effective than placebo, and 2 RCTs have shown that fluoxetine and sertraline (Zoloft) are comparable to amitriptyline.³ Single RCTs conducted on duloxetine and milnacipran, new SNRIs, demonstrated them to be more effective than placebo in improving pain and scores on the Fibromyalgia Impact Questionnaire (FIQ).³ Three RCTs have shown that tramadol (with or without acetaminophen) is more effective than placebo in improving pain, number of tender points and FIQ score.³

A single RCT has demonstrated that pregabalin (Lyrica), a new anticonvulsant, reduces pain more than placebo.³

Among nonpharmacological interventions, aerobic exercise and cognitive behavioral therapy have the strongest evidence of effectiveness. A systematic review assessing various exercise programs on symptoms of fibromyalgia showed that aerobic exercise produces short-term improvements in cardiovascular fitness, tender-point pressure pain threshold, and patient- and physicianrated global well-being. Three of these trials included long-term follow-up of the exercise group participants. Patients who continued exercising maintained their improved physical functioning.⁴

Cognitive behavioral therapy has been shown to reduce symptoms in 5 RCTs.3 Combining cognitive behavioral therapy with education and exercise has also been effective in 5 additional RCTs.³ Some evidence suggests that acupuncture, massage, warm baths, and biofeedback are effective, but this is limited because of methodological issues in the studies that have been conducted to date.³

Recommendations from others

A recently published evidence-based guideline sponsored by the American Pain Society recommends low-dose TCAs, cyclobenzaprine, cardiovascular exercise, and cognitive behavioral therapy alone or with exercise as first-line therapy along with patient education and treatment of comorbid conditions. For patients that do not improve, it recommends a trial of an SSRI, an SNRI, tramadol, an anticonvulsant, combination medications, or referral.³

Evidence summary

Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.¹ Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.

Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.² Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.

A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.³ At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.

A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.⁴ Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.

Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.⁵ Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.⁶

Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.⁷ A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.⁸

Recommendations from others

The American Academy of Pediatrics (AAP) recommends that:

• All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg⁹
• All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk¹⁰
• All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.

The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.¹¹

The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.¹²

The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.¹³

Evidence summary

Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.¹ Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.

Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.² Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.

A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.³ At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.

A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.⁴ Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.

Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.⁵ Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.⁶

Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.⁷ A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.⁸

Recommendations from others

The American Academy of Pediatrics (AAP) recommends that:

• All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg⁹
• All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk¹⁰
• All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.

The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.¹¹

The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.¹²

The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.¹³

Evidence summary

Vitamin K. The Cochrane Database of Systematic Reviews looked at randomized trials to determine the effectiveness of vitamin K prophylaxis in preventing classic hemorrhagic disease of the newborn.¹ Two trials demonstrated that a single dose of intramuscular vitamin K reduced clinical bleeding at 1 to 7 days. Oral vitamin K has been studied for its effects on biochemical indices of coagulation status, but not for its clinical effects on bleeding. A single oral vitamin K dose at birth resulted in lower vitamin K levels at 2 weeks and 1 month, compared with a single dose of intramuscular vitamin K at birth.

Iron. The iron status of exclusively breastfed infants vs formula-fed infants was evaluated in a nonrandomized cohort study.² Twenty-five healthy, breastfed infants and 15 healthy infants fed high-iron formula were followed for 9 months. No differences in mean hemoglobin values were seen at any age between the 2 groups.

A randomized controlled trial investigated the efficacy of daily and weekly iron supplementation on iron status in 67 exclusively breastfed infants.³ At age 4 months the infants were randomized into 3 groups: daily iron, weekly iron, and no iron. No significant differences were detected in the mean weight, height, and head circumference among the groups. The mean values of hemoglobin, mean corpuscular volume, serum iron, and transferrin saturation were similar among all the groups at ages 5, 6, and 7 months.

A randomized, double-blind, placebo-controlled iron supplementation trial involved 214 exclusively breastfed infants from 4 to 9 months of age in Sweden and Honduras.⁴ Iron supplementation did not affect weight gain in the groups, but length gain from ages 4 to 9 months was less in the iron-supplemented groups than in the placebo group (P<.05 for placebo vs Fe). This effect was greater in Sweden, and only existed in Honduras for infants aged 4 to 6 months with initial mean Hgb of at least 11 mg/dL. The researchers conclude that iron supplementation may pose risks in iron-replete infants.

Vitamin D. A case review of nutritional rickets in North Carolina between 1990 and 1999 found that all 30 patients identified were breastfed African American infants.⁵ Among the 166 published cases of rickets in the US from 1986 to 2003, 83% were categorized as African American or black. Ninety-six percent of cases were breastfed.⁶

Fluoride. No infant under 6 months of age should receive fluoride supplementation to prevent dental caries because of the risk of enamel fluorosis.⁷ A systematic review that evaluated fluoride for preventing dental caries in primary teeth in children aged <5 years found 6 small clinical trials. Although the studies were not of high quality, they consistently showed that the incidence of caries was reduced by 32% to 72%.⁸

Recommendations from others

The American Academy of Pediatrics (AAP) recommends that:

• All newborns receive vitamin K as an intramuscular dose of 0.5 to 1 mg⁹
• All full-term appropriate-for-gestational-age breastfed infants receive a supplemental source of iron starting at 4 to 6 months of age, preferably from iron-enriched complementary foods. Infants should only receive formula fortified with 10 to 12 mg/L for weaning or supplementing breastmilk¹⁰
• All infants, including those exclusively breastfed, should have a minimum intake of 200 IU of vitamin D per day starting in the first 2 months of life.

The National Academy of Sciences recommends 200 IU of vitamin D daily for all normal infants, children, and adolescents.¹¹

The US Preventative Services Task Force (USPSTF) states evidence is insufficient to recommend for or against the routine use of iron supplements for healthy infants.¹²

The USPSTF, AAP, and the American Academy of Pediatric Dentistry recommends 0.25 mg/d of fluoride supplement for children ages 6 months to 3 years if the fluoride concentration in the community drinking water is less than 0.3 ppm. Older children may benefit from supplements if the fluoride concentration is between 0.3 and 0.6 ppm.¹³

Evidence summary

Many Lyme disease serologic tests are ordered inappropriately, often influenced by patient demand. In a prospective, crosssectional survey of Wisconsin physicians, only 20% of ordered tests were appropriate. Tests were classified as inappropriate if ordered (1) for asymptomatic patients, (2) for patients with physician-diagnosed erythema migrans, (3) for patients receiving empiric antibiotic treatment, or (4) as test-of-cure.³

The positive predictive value of a test the likelihood that a person who tests positive actually has the disease) depends on the prevalence of that condition. Available Lyme serology tests vary in their sensitivity and specificity. Selecting patients with signs or symptoms of disseminated Lyme disease theoretically increases the pretest probability, thus improving the positive predictive value of the test.

In a prospective study of 46 treated patients with culture-proven erythema migrans, 91% had a positive ELISA or immunoglobulin M (IgM) immunoblot result at 8 to 14 days after baseline. Peak IgM antibody levels were seen at this time among patients with localized or disseminated disease. Detectable IgM levels appeared within a few days of onset of erythema migrans and were found in most individuals with disease of at least 2 weeks duration.⁴ Another small study of 55 treated patients similarly found peak antibody response at 8 to 12 days into treatment.⁵

A recent review article recommends serologic testing for patients with a moderate pretest probability (ie, patients with objective signs of Lyme disease from a highly or moderately endemic area). Patients from highly endemic areas who present with erythema migrans have a high enough pretest probability to make the diagnosis of Lyme disease without serologic testing.⁶

Recommendations from others

The Centers for Disease Control and Prevention (CDC) defines a case of Lyme disease as physician-diagnosed erythema migrans ≥5 cm in diameter, or at least 1 objective manifestation of late Lyme disease (eg, musculoskeletal, cardiovascular, or neurologic symptoms) with laboratory confirmation of Borrelia burgdorferi infection using a 2-tiered assay.⁷ Thus, the CDC notes that Lyme disease is a clinical diagnosis and accordingly recommends against testing patients who are asymptomatic or who have proven disease (erythema migrans).

The American College of Physicians Clinical Guidelines recommend performing serologic testing for patients with an intermediate pretest probability between 20% and 80%.⁸ Low pretest probability scenarios (<20%) include patients with nonspecific symptoms of myalgia such as fatigue, stiffness, and diffuse muscle aches and tenderness. High pretest probability scenarios (>80%) include patients with erythema migrans. Intermediate pretest probability scenarios include patients with possible disseminated Lyme disease findings such as recurrent oligoarticular inflammatory arthritis (TABLE). Cost effectiveness analyses support this approach.⁹

Guidelines established by a joint CDC/Association of State and Territorial Public Health Laboratory Directors commission require a 2-tiered laboratory approach to diagnosis.² A highly sensitive initial test (ELISA) is followed by a highly specific supplemental test (Western blot). These guidelines have good clinical applicability (overall sensitivity 50%, specificity 100%).¹⁰ The relatively low sensitivity is likely due to antibiotic treatment of several subjects resulting in reduced humoral response.

TABLE
Pretest probability scenarios for suspected Lyme disease

Evidence summary

Many Lyme disease serologic tests are ordered inappropriately, often influenced by patient demand. In a prospective, crosssectional survey of Wisconsin physicians, only 20% of ordered tests were appropriate. Tests were classified as inappropriate if ordered (1) for asymptomatic patients, (2) for patients with physician-diagnosed erythema migrans, (3) for patients receiving empiric antibiotic treatment, or (4) as test-of-cure.³

The positive predictive value of a test the likelihood that a person who tests positive actually has the disease) depends on the prevalence of that condition. Available Lyme serology tests vary in their sensitivity and specificity. Selecting patients with signs or symptoms of disseminated Lyme disease theoretically increases the pretest probability, thus improving the positive predictive value of the test.

In a prospective study of 46 treated patients with culture-proven erythema migrans, 91% had a positive ELISA or immunoglobulin M (IgM) immunoblot result at 8 to 14 days after baseline. Peak IgM antibody levels were seen at this time among patients with localized or disseminated disease. Detectable IgM levels appeared within a few days of onset of erythema migrans and were found in most individuals with disease of at least 2 weeks duration.⁴ Another small study of 55 treated patients similarly found peak antibody response at 8 to 12 days into treatment.⁵

A recent review article recommends serologic testing for patients with a moderate pretest probability (ie, patients with objective signs of Lyme disease from a highly or moderately endemic area). Patients from highly endemic areas who present with erythema migrans have a high enough pretest probability to make the diagnosis of Lyme disease without serologic testing.⁶

Recommendations from others

The Centers for Disease Control and Prevention (CDC) defines a case of Lyme disease as physician-diagnosed erythema migrans ≥5 cm in diameter, or at least 1 objective manifestation of late Lyme disease (eg, musculoskeletal, cardiovascular, or neurologic symptoms) with laboratory confirmation of Borrelia burgdorferi infection using a 2-tiered assay.⁷ Thus, the CDC notes that Lyme disease is a clinical diagnosis and accordingly recommends against testing patients who are asymptomatic or who have proven disease (erythema migrans).

The American College of Physicians Clinical Guidelines recommend performing serologic testing for patients with an intermediate pretest probability between 20% and 80%.⁸ Low pretest probability scenarios (<20%) include patients with nonspecific symptoms of myalgia such as fatigue, stiffness, and diffuse muscle aches and tenderness. High pretest probability scenarios (>80%) include patients with erythema migrans. Intermediate pretest probability scenarios include patients with possible disseminated Lyme disease findings such as recurrent oligoarticular inflammatory arthritis (TABLE). Cost effectiveness analyses support this approach.⁹

Guidelines established by a joint CDC/Association of State and Territorial Public Health Laboratory Directors commission require a 2-tiered laboratory approach to diagnosis.² A highly sensitive initial test (ELISA) is followed by a highly specific supplemental test (Western blot). These guidelines have good clinical applicability (overall sensitivity 50%, specificity 100%).¹⁰ The relatively low sensitivity is likely due to antibiotic treatment of several subjects resulting in reduced humoral response.

TABLE
Pretest probability scenarios for suspected Lyme disease

Evidence summary

Many Lyme disease serologic tests are ordered inappropriately, often influenced by patient demand. In a prospective, crosssectional survey of Wisconsin physicians, only 20% of ordered tests were appropriate. Tests were classified as inappropriate if ordered (1) for asymptomatic patients, (2) for patients with physician-diagnosed erythema migrans, (3) for patients receiving empiric antibiotic treatment, or (4) as test-of-cure.³

The positive predictive value of a test the likelihood that a person who tests positive actually has the disease) depends on the prevalence of that condition. Available Lyme serology tests vary in their sensitivity and specificity. Selecting patients with signs or symptoms of disseminated Lyme disease theoretically increases the pretest probability, thus improving the positive predictive value of the test.

In a prospective study of 46 treated patients with culture-proven erythema migrans, 91% had a positive ELISA or immunoglobulin M (IgM) immunoblot result at 8 to 14 days after baseline. Peak IgM antibody levels were seen at this time among patients with localized or disseminated disease. Detectable IgM levels appeared within a few days of onset of erythema migrans and were found in most individuals with disease of at least 2 weeks duration.⁴ Another small study of 55 treated patients similarly found peak antibody response at 8 to 12 days into treatment.⁵

A recent review article recommends serologic testing for patients with a moderate pretest probability (ie, patients with objective signs of Lyme disease from a highly or moderately endemic area). Patients from highly endemic areas who present with erythema migrans have a high enough pretest probability to make the diagnosis of Lyme disease without serologic testing.⁶

Recommendations from others

The Centers for Disease Control and Prevention (CDC) defines a case of Lyme disease as physician-diagnosed erythema migrans ≥5 cm in diameter, or at least 1 objective manifestation of late Lyme disease (eg, musculoskeletal, cardiovascular, or neurologic symptoms) with laboratory confirmation of Borrelia burgdorferi infection using a 2-tiered assay.⁷ Thus, the CDC notes that Lyme disease is a clinical diagnosis and accordingly recommends against testing patients who are asymptomatic or who have proven disease (erythema migrans).

The American College of Physicians Clinical Guidelines recommend performing serologic testing for patients with an intermediate pretest probability between 20% and 80%.⁸ Low pretest probability scenarios (<20%) include patients with nonspecific symptoms of myalgia such as fatigue, stiffness, and diffuse muscle aches and tenderness. High pretest probability scenarios (>80%) include patients with erythema migrans. Intermediate pretest probability scenarios include patients with possible disseminated Lyme disease findings such as recurrent oligoarticular inflammatory arthritis (TABLE). Cost effectiveness analyses support this approach.⁹

Guidelines established by a joint CDC/Association of State and Territorial Public Health Laboratory Directors commission require a 2-tiered laboratory approach to diagnosis.² A highly sensitive initial test (ELISA) is followed by a highly specific supplemental test (Western blot). These guidelines have good clinical applicability (overall sensitivity 50%, specificity 100%).¹⁰ The relatively low sensitivity is likely due to antibiotic treatment of several subjects resulting in reduced humoral response.

TABLE
Pretest probability scenarios for suspected Lyme disease

Evidence summary

Even though the chest x-ray is as close to a gold standard as we have for diagnosing pneumonia (FIGURE), in practice it is only ordered about 11% of the time.³ Individual clinical findings such as pulse above 100 beats per minute, respiratory rate above 25 breaths per minute, temperature above 99.9°F, local dullness to percussion, rales, asymmetric respirations, pleural rubs, egophony, increased fremitus, and cachexia are weak predictors of pneumonia, being present in 4% to 28% of radiographically proven pneumonia.¹ Individual symptoms such as chills, night sweats, fever, and sputum production are found in 31% to 79% of those with pneumonia, but also in 18% to 62% of those without pneumonia. Therefore prediction rules, using combinations of statistically significant factors, have been developed to help us decide when to order a chest x-ray to diagnose pneumonia.

Unfortunately, almost all studies that have developed prediction rules preselected higher-risk patients—those who had already been selected to get a chest x-ray (based on unknown signs and symptoms).^4-6 The signs and symptoms that predict pneumonia for patients already selected for a chest x-ray may be different than for unselected patients. These studies also assume that physician judgment in ordering a chest x-ray is 100% sensitive and thus that all patients with pneumonia have been correctly identified.

Only 2 studies have done chest x-rays on all nonpregnant adults with a first visit for a cough of less than 4 weeks duration and no other exclusion criteria.^1,7 Physicians indicated that they would have wanted to order chest x-rays in 12% to 15% of those patients (similar to national statistics), but they would have detected only one third of all the pneumonias. One of these studies looked at signs and symptoms and did a stepwise discriminant analysis with those factors that were significant for pneumonia and then assigned point values to them (TABLE 1 AND 2).¹ By limiting chest x-rays to those patients with a clinical score of 1 or greater, 13% of patients would have a chest x-ray with 59% of pneumonias detected—almost twice as many as detected without the prediction rule.

One problem with the application of prediction rules is that they are always associated with missed pneumonias. Not much is known about the pneumonias that would be missed by applying the prediction rule or, for that matter, those that are missed using physician judgment. In the above study, before seeing the results of the x-rays, only 50% of the pneumonia patients would have been prescribed antibiotics. In another study where patients with lower respiratory tract infection all received radiographs but the treating physicians did not see the x-ray results, only half of the patients with radiographic changes consistent with pneumonia were given antibiotics.⁸ Surprisingly, those patients with infection changes on chest x-ray were no more likely to reconsult than those without those changes, implying that a certain percentage of outpatient pneumonias are self-limiting.⁷

FIGURE
When to order chest x-ray?

TABLE 1
Signs and symptoms significant for pneumonia

TABLE 2
Distribution of point scores for pneumonia and non-pneumonia groups

Recommendations from others

The Infectious Disease Society of America, the American Thoracic Society, the Canadian Infectious Disease Society and the Canadian Thoracic Society, and the Centers for Disease Control and Prevention all recommend a chest x-ray for patients for whom signs and symptoms suggest a pneumonia, but they do not give any guidance as to which signs and symptoms are significant.^9-12 The British Thoracic Society does not recommend radiography for patients with suspected pneumonia among outpatients.¹³ The European Respiratory Society only recommends a chest x-ray for those patients with failure of first-time empirical therapy or focal chest signs; a chest x-ray may also be indicated for those who are aged ≥65 years, are institutionalized, are alcoholics, have possibly aspirated, have been hospitalized within the previous year for pneumonia, or have significant comorbidities.¹⁴

Evidence summary

Even though the chest x-ray is as close to a gold standard as we have for diagnosing pneumonia (FIGURE), in practice it is only ordered about 11% of the time.³ Individual clinical findings such as pulse above 100 beats per minute, respiratory rate above 25 breaths per minute, temperature above 99.9°F, local dullness to percussion, rales, asymmetric respirations, pleural rubs, egophony, increased fremitus, and cachexia are weak predictors of pneumonia, being present in 4% to 28% of radiographically proven pneumonia.¹ Individual symptoms such as chills, night sweats, fever, and sputum production are found in 31% to 79% of those with pneumonia, but also in 18% to 62% of those without pneumonia. Therefore prediction rules, using combinations of statistically significant factors, have been developed to help us decide when to order a chest x-ray to diagnose pneumonia.

Unfortunately, almost all studies that have developed prediction rules preselected higher-risk patients—those who had already been selected to get a chest x-ray (based on unknown signs and symptoms).^4-6 The signs and symptoms that predict pneumonia for patients already selected for a chest x-ray may be different than for unselected patients. These studies also assume that physician judgment in ordering a chest x-ray is 100% sensitive and thus that all patients with pneumonia have been correctly identified.

Only 2 studies have done chest x-rays on all nonpregnant adults with a first visit for a cough of less than 4 weeks duration and no other exclusion criteria.^1,7 Physicians indicated that they would have wanted to order chest x-rays in 12% to 15% of those patients (similar to national statistics), but they would have detected only one third of all the pneumonias. One of these studies looked at signs and symptoms and did a stepwise discriminant analysis with those factors that were significant for pneumonia and then assigned point values to them (TABLE 1 AND 2).¹ By limiting chest x-rays to those patients with a clinical score of 1 or greater, 13% of patients would have a chest x-ray with 59% of pneumonias detected—almost twice as many as detected without the prediction rule.

One problem with the application of prediction rules is that they are always associated with missed pneumonias. Not much is known about the pneumonias that would be missed by applying the prediction rule or, for that matter, those that are missed using physician judgment. In the above study, before seeing the results of the x-rays, only 50% of the pneumonia patients would have been prescribed antibiotics. In another study where patients with lower respiratory tract infection all received radiographs but the treating physicians did not see the x-ray results, only half of the patients with radiographic changes consistent with pneumonia were given antibiotics.⁸ Surprisingly, those patients with infection changes on chest x-ray were no more likely to reconsult than those without those changes, implying that a certain percentage of outpatient pneumonias are self-limiting.⁷

FIGURE
When to order chest x-ray?

TABLE 1
Signs and symptoms significant for pneumonia

TABLE 2
Distribution of point scores for pneumonia and non-pneumonia groups

Recommendations from others

The Infectious Disease Society of America, the American Thoracic Society, the Canadian Infectious Disease Society and the Canadian Thoracic Society, and the Centers for Disease Control and Prevention all recommend a chest x-ray for patients for whom signs and symptoms suggest a pneumonia, but they do not give any guidance as to which signs and symptoms are significant.^9-12 The British Thoracic Society does not recommend radiography for patients with suspected pneumonia among outpatients.¹³ The European Respiratory Society only recommends a chest x-ray for those patients with failure of first-time empirical therapy or focal chest signs; a chest x-ray may also be indicated for those who are aged ≥65 years, are institutionalized, are alcoholics, have possibly aspirated, have been hospitalized within the previous year for pneumonia, or have significant comorbidities.¹⁴

Evidence summary

Even though the chest x-ray is as close to a gold standard as we have for diagnosing pneumonia (FIGURE), in practice it is only ordered about 11% of the time.³ Individual clinical findings such as pulse above 100 beats per minute, respiratory rate above 25 breaths per minute, temperature above 99.9°F, local dullness to percussion, rales, asymmetric respirations, pleural rubs, egophony, increased fremitus, and cachexia are weak predictors of pneumonia, being present in 4% to 28% of radiographically proven pneumonia.¹ Individual symptoms such as chills, night sweats, fever, and sputum production are found in 31% to 79% of those with pneumonia, but also in 18% to 62% of those without pneumonia. Therefore prediction rules, using combinations of statistically significant factors, have been developed to help us decide when to order a chest x-ray to diagnose pneumonia.

Unfortunately, almost all studies that have developed prediction rules preselected higher-risk patients—those who had already been selected to get a chest x-ray (based on unknown signs and symptoms).^4-6 The signs and symptoms that predict pneumonia for patients already selected for a chest x-ray may be different than for unselected patients. These studies also assume that physician judgment in ordering a chest x-ray is 100% sensitive and thus that all patients with pneumonia have been correctly identified.

Only 2 studies have done chest x-rays on all nonpregnant adults with a first visit for a cough of less than 4 weeks duration and no other exclusion criteria.^1,7 Physicians indicated that they would have wanted to order chest x-rays in 12% to 15% of those patients (similar to national statistics), but they would have detected only one third of all the pneumonias. One of these studies looked at signs and symptoms and did a stepwise discriminant analysis with those factors that were significant for pneumonia and then assigned point values to them (TABLE 1 AND 2).¹ By limiting chest x-rays to those patients with a clinical score of 1 or greater, 13% of patients would have a chest x-ray with 59% of pneumonias detected—almost twice as many as detected without the prediction rule.

One problem with the application of prediction rules is that they are always associated with missed pneumonias. Not much is known about the pneumonias that would be missed by applying the prediction rule or, for that matter, those that are missed using physician judgment. In the above study, before seeing the results of the x-rays, only 50% of the pneumonia patients would have been prescribed antibiotics. In another study where patients with lower respiratory tract infection all received radiographs but the treating physicians did not see the x-ray results, only half of the patients with radiographic changes consistent with pneumonia were given antibiotics.⁸ Surprisingly, those patients with infection changes on chest x-ray were no more likely to reconsult than those without those changes, implying that a certain percentage of outpatient pneumonias are self-limiting.⁷

FIGURE
When to order chest x-ray?

TABLE 1
Signs and symptoms significant for pneumonia

TABLE 2
Distribution of point scores for pneumonia and non-pneumonia groups

Recommendations from others

The Infectious Disease Society of America, the American Thoracic Society, the Canadian Infectious Disease Society and the Canadian Thoracic Society, and the Centers for Disease Control and Prevention all recommend a chest x-ray for patients for whom signs and symptoms suggest a pneumonia, but they do not give any guidance as to which signs and symptoms are significant.^9-12 The British Thoracic Society does not recommend radiography for patients with suspected pneumonia among outpatients.¹³ The European Respiratory Society only recommends a chest x-ray for those patients with failure of first-time empirical therapy or focal chest signs; a chest x-ray may also be indicated for those who are aged ≥65 years, are institutionalized, are alcoholics, have possibly aspirated, have been hospitalized within the previous year for pneumonia, or have significant comorbidities.¹⁴

Evidence summary

Oral contraceptives (OC) are taken by approximately 70 million women worldwide.² Studies suggest there is extreme variation in plasma concentrations of active hormone between individuals, even without any significant drug interactions.^2,7 Current preparations contain lower doses of estrogen; a drug interaction causing decreased efficacy of OCs may be more likely.^1,2,4,5

More than 200 occurrences have been reported anecdotally, in adverse-event monitoring systems, and in retrospective surveys of OC failure for women treated with various antibiotics. But no prospective RCTs have been done, and most of the retrospective case series have not used control groups.¹ All the pharmacokinetic and retrospective studies have a small sample size, which may conceal an interaction within the normal OC failure rate.^1,2 Given this, 4 retrospective surveys on women taking OCs who were treated with antibiotics (erythromycin, tetracycline, minocycline, penicillin, ampicillin, sulfa, cephalosporins) found OC failure rates of 1.2% to 1.6%, within the range for typical populations.¹ These data are subject to recall bias and underreporting of poor compliance.

Multiple studies have looked at OC serum levels with and without antibiotic treatment.¹ These studies show that the coadministration of antibiotics (ampicillin, tetracycline, doxycycline, metronidazole, erythromycin, clarithromycin, temafloxacin, fluconazole, ciprofloxacin, or ofloxacin) did not reduce serum levels of either the estrogen or progestin components of the oral contraceptives.^1,2 Rifampin is a potent inducer of the cytochrome P450 system, capable of reducing serum estrogen and progestin levels, and a small-scale study has suggested breakthrough ovulation among 2 of 9 women taking oral contraceptives and rifampin.^2,8

It is possible, however, that a true interaction between antibiotics and OCs may only manifest itself in the very small subset of women who have unusually low steroid hormone levels.^1-3 The women most likely to have pill failure are those with low rates of ethinyl estradiol hydroxylation, high rates of hepatic conjugation, low plasma concentrations of ethinyl estradiol, extensive intestinal hydrolysis of estrogen conjugates, or gut flora particularly susceptible to the antibiotic.^1,3 These women may be identified by symptoms of breakthrough bleeding, cramping, nausea, vomiting or diarrhea, or by unwanted pregnancy.^2,3 Unfortunately, they cannot be identified by any routine diagnostic tests. The most conservative approach emphasizes patient education and additional forms of nonhormonal contraception for any woman on OCs during any antibiotic therapy and for at least 1 week after treatment.^1,3

Recommendations from others

Williams Obstetrics (2001) states that some antibiotics still have in their labeling that they may reduce the effectiveness of OCs, but that this is likely not true.⁹ They do not have a recommendation on how to handle this. The MMWR Recommendations and Reports (2003) recommend that women of reproductive potential on OCs who are also taking rifampin should add a barrier method of contraception.¹⁰ The World Health Organization (WHO) states that there have been suspicions that broad-spectrum antibiotics may lower OC effectiveness based on case reports, but that pregnancy rates are similar among women on OCs and women on both OCs and antibiotics.¹¹ According to the WHO 2003 Expert Working Group, broad-spectrum antibiotics are in Medical Eligibility Criteria category 1, which allows use in any circumstances.¹¹

Evidence summary

Oral contraceptives (OC) are taken by approximately 70 million women worldwide.² Studies suggest there is extreme variation in plasma concentrations of active hormone between individuals, even without any significant drug interactions.^2,7 Current preparations contain lower doses of estrogen; a drug interaction causing decreased efficacy of OCs may be more likely.^1,2,4,5

More than 200 occurrences have been reported anecdotally, in adverse-event monitoring systems, and in retrospective surveys of OC failure for women treated with various antibiotics. But no prospective RCTs have been done, and most of the retrospective case series have not used control groups.¹ All the pharmacokinetic and retrospective studies have a small sample size, which may conceal an interaction within the normal OC failure rate.^1,2 Given this, 4 retrospective surveys on women taking OCs who were treated with antibiotics (erythromycin, tetracycline, minocycline, penicillin, ampicillin, sulfa, cephalosporins) found OC failure rates of 1.2% to 1.6%, within the range for typical populations.¹ These data are subject to recall bias and underreporting of poor compliance.

Multiple studies have looked at OC serum levels with and without antibiotic treatment.¹ These studies show that the coadministration of antibiotics (ampicillin, tetracycline, doxycycline, metronidazole, erythromycin, clarithromycin, temafloxacin, fluconazole, ciprofloxacin, or ofloxacin) did not reduce serum levels of either the estrogen or progestin components of the oral contraceptives.^1,2 Rifampin is a potent inducer of the cytochrome P450 system, capable of reducing serum estrogen and progestin levels, and a small-scale study has suggested breakthrough ovulation among 2 of 9 women taking oral contraceptives and rifampin.^2,8

It is possible, however, that a true interaction between antibiotics and OCs may only manifest itself in the very small subset of women who have unusually low steroid hormone levels.^1-3 The women most likely to have pill failure are those with low rates of ethinyl estradiol hydroxylation, high rates of hepatic conjugation, low plasma concentrations of ethinyl estradiol, extensive intestinal hydrolysis of estrogen conjugates, or gut flora particularly susceptible to the antibiotic.^1,3 These women may be identified by symptoms of breakthrough bleeding, cramping, nausea, vomiting or diarrhea, or by unwanted pregnancy.^2,3 Unfortunately, they cannot be identified by any routine diagnostic tests. The most conservative approach emphasizes patient education and additional forms of nonhormonal contraception for any woman on OCs during any antibiotic therapy and for at least 1 week after treatment.^1,3

Recommendations from others

Williams Obstetrics (2001) states that some antibiotics still have in their labeling that they may reduce the effectiveness of OCs, but that this is likely not true.⁹ They do not have a recommendation on how to handle this. The MMWR Recommendations and Reports (2003) recommend that women of reproductive potential on OCs who are also taking rifampin should add a barrier method of contraception.¹⁰ The World Health Organization (WHO) states that there have been suspicions that broad-spectrum antibiotics may lower OC effectiveness based on case reports, but that pregnancy rates are similar among women on OCs and women on both OCs and antibiotics.¹¹ According to the WHO 2003 Expert Working Group, broad-spectrum antibiotics are in Medical Eligibility Criteria category 1, which allows use in any circumstances.¹¹

Evidence summary

Oral contraceptives (OC) are taken by approximately 70 million women worldwide.² Studies suggest there is extreme variation in plasma concentrations of active hormone between individuals, even without any significant drug interactions.^2,7 Current preparations contain lower doses of estrogen; a drug interaction causing decreased efficacy of OCs may be more likely.^1,2,4,5

More than 200 occurrences have been reported anecdotally, in adverse-event monitoring systems, and in retrospective surveys of OC failure for women treated with various antibiotics. But no prospective RCTs have been done, and most of the retrospective case series have not used control groups.¹ All the pharmacokinetic and retrospective studies have a small sample size, which may conceal an interaction within the normal OC failure rate.^1,2 Given this, 4 retrospective surveys on women taking OCs who were treated with antibiotics (erythromycin, tetracycline, minocycline, penicillin, ampicillin, sulfa, cephalosporins) found OC failure rates of 1.2% to 1.6%, within the range for typical populations.¹ These data are subject to recall bias and underreporting of poor compliance.

Multiple studies have looked at OC serum levels with and without antibiotic treatment.¹ These studies show that the coadministration of antibiotics (ampicillin, tetracycline, doxycycline, metronidazole, erythromycin, clarithromycin, temafloxacin, fluconazole, ciprofloxacin, or ofloxacin) did not reduce serum levels of either the estrogen or progestin components of the oral contraceptives.^1,2 Rifampin is a potent inducer of the cytochrome P450 system, capable of reducing serum estrogen and progestin levels, and a small-scale study has suggested breakthrough ovulation among 2 of 9 women taking oral contraceptives and rifampin.^2,8

It is possible, however, that a true interaction between antibiotics and OCs may only manifest itself in the very small subset of women who have unusually low steroid hormone levels.^1-3 The women most likely to have pill failure are those with low rates of ethinyl estradiol hydroxylation, high rates of hepatic conjugation, low plasma concentrations of ethinyl estradiol, extensive intestinal hydrolysis of estrogen conjugates, or gut flora particularly susceptible to the antibiotic.^1,3 These women may be identified by symptoms of breakthrough bleeding, cramping, nausea, vomiting or diarrhea, or by unwanted pregnancy.^2,3 Unfortunately, they cannot be identified by any routine diagnostic tests. The most conservative approach emphasizes patient education and additional forms of nonhormonal contraception for any woman on OCs during any antibiotic therapy and for at least 1 week after treatment.^1,3

Recommendations from others

Williams Obstetrics (2001) states that some antibiotics still have in their labeling that they may reduce the effectiveness of OCs, but that this is likely not true.⁹ They do not have a recommendation on how to handle this. The MMWR Recommendations and Reports (2003) recommend that women of reproductive potential on OCs who are also taking rifampin should add a barrier method of contraception.¹⁰ The World Health Organization (WHO) states that there have been suspicions that broad-spectrum antibiotics may lower OC effectiveness based on case reports, but that pregnancy rates are similar among women on OCs and women on both OCs and antibiotics.¹¹ According to the WHO 2003 Expert Working Group, broad-spectrum antibiotics are in Medical Eligibility Criteria category 1, which allows use in any circumstances.¹¹