Paul Crawford, MD

Evidence summary

Travelers to malaria-endemic areas should avoid mosquito bites by using netting and repellents, and use chemoprophylaxis to prevent infection.

Although no drug regimen guarantees protection against malaria, physicians should prescribe 1 of several options based on the location of travel, the susceptibility of indigenous P falciparum, and the side-effect profile.¹

Timing and dosage of prophylactic drugs

Prophylactic medications must be started at different times before travel, but for some medications the optimal time to initiate treatment is unclear. Evidence-based recommendations^2,3 with consideration for side-effect profiles are given in the TABLE.

In contrast to the pretreatment times for all other malarial prophylaxes, the generally accepted pretreatment time for mefloquine is 1 to 2 weeks before entering a risk area. However, this may still be inadequate due to the drug’s long half-life, which results in a long delay in reaching therapeutic blood levels.⁴ The evidence indicates that mefloquine should be started at least 2, and as many as 7, weeks before travel.

The standard recommended dose of 250 mg/week of mefloquine “produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached only after 7 to 10 weeks.”⁴ One study of 293 children under the age of 5 years in Malawi found that plasma concentrations of mefloquine were below prophylactic level (500 mcg/mL) against P falciparum until the fourth to seventh week of once-weekly dosing (P<.0003).⁵

One way of reaching prophylactic levels earlier would be to give mefloquine 250 mg daily for 3 days followed by 250 mg weekly.⁴ A safety study of 157 healthy US Marine volunteers showed that preloading achieves prophylactic blood levels of mefloquine by the third day while weekly mefloquine is subprophylactic until the fifth week.⁴

While a study of the long-term use of mefloquine in 421 healthy Peace Corps volunteers has shown it to be safe,⁶ clinical trials and case reports indicate that a loading dose of mefloquine is associated with adverse drug events, which include neuropsychiatric and gastrointestinal symptoms.^4,7

TABLE
Evidence-based recommendations for prevention of malaria^2-3,8

Recommendations from others

The World Health Organization (WHO) states that “weekly mefloquine should be started at least 1 week, but preferably 2–3 weeks before departure, to achieve higher pre-travel blood levels and to allow side effects to be detected before travel so that possible alternatives can be considered.”⁸

Centers for Disease Control and Prevention recommendations integrate recommendations from WHO and Cochrane.

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Travelers to malaria-endemic areas should avoid mosquito bites by using netting and repellents, and use chemoprophylaxis to prevent infection.

Although no drug regimen guarantees protection against malaria, physicians should prescribe 1 of several options based on the location of travel, the susceptibility of indigenous P falciparum, and the side-effect profile.¹

Timing and dosage of prophylactic drugs

Prophylactic medications must be started at different times before travel, but for some medications the optimal time to initiate treatment is unclear. Evidence-based recommendations^2,3 with consideration for side-effect profiles are given in the TABLE.

In contrast to the pretreatment times for all other malarial prophylaxes, the generally accepted pretreatment time for mefloquine is 1 to 2 weeks before entering a risk area. However, this may still be inadequate due to the drug’s long half-life, which results in a long delay in reaching therapeutic blood levels.⁴ The evidence indicates that mefloquine should be started at least 2, and as many as 7, weeks before travel.

The standard recommended dose of 250 mg/week of mefloquine “produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached only after 7 to 10 weeks.”⁴ One study of 293 children under the age of 5 years in Malawi found that plasma concentrations of mefloquine were below prophylactic level (500 mcg/mL) against P falciparum until the fourth to seventh week of once-weekly dosing (P<.0003).⁵

One way of reaching prophylactic levels earlier would be to give mefloquine 250 mg daily for 3 days followed by 250 mg weekly.⁴ A safety study of 157 healthy US Marine volunteers showed that preloading achieves prophylactic blood levels of mefloquine by the third day while weekly mefloquine is subprophylactic until the fifth week.⁴

While a study of the long-term use of mefloquine in 421 healthy Peace Corps volunteers has shown it to be safe,⁶ clinical trials and case reports indicate that a loading dose of mefloquine is associated with adverse drug events, which include neuropsychiatric and gastrointestinal symptoms.^4,7

TABLE
Evidence-based recommendations for prevention of malaria^2-3,8

Recommendations from others

The World Health Organization (WHO) states that “weekly mefloquine should be started at least 1 week, but preferably 2–3 weeks before departure, to achieve higher pre-travel blood levels and to allow side effects to be detected before travel so that possible alternatives can be considered.”⁸

Centers for Disease Control and Prevention recommendations integrate recommendations from WHO and Cochrane.

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Travelers to malaria-endemic areas should avoid mosquito bites by using netting and repellents, and use chemoprophylaxis to prevent infection.

Although no drug regimen guarantees protection against malaria, physicians should prescribe 1 of several options based on the location of travel, the susceptibility of indigenous P falciparum, and the side-effect profile.¹

Timing and dosage of prophylactic drugs

Prophylactic medications must be started at different times before travel, but for some medications the optimal time to initiate treatment is unclear. Evidence-based recommendations^2,3 with consideration for side-effect profiles are given in the TABLE.

In contrast to the pretreatment times for all other malarial prophylaxes, the generally accepted pretreatment time for mefloquine is 1 to 2 weeks before entering a risk area. However, this may still be inadequate due to the drug’s long half-life, which results in a long delay in reaching therapeutic blood levels.⁴ The evidence indicates that mefloquine should be started at least 2, and as many as 7, weeks before travel.

The standard recommended dose of 250 mg/week of mefloquine “produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached only after 7 to 10 weeks.”⁴ One study of 293 children under the age of 5 years in Malawi found that plasma concentrations of mefloquine were below prophylactic level (500 mcg/mL) against P falciparum until the fourth to seventh week of once-weekly dosing (P<.0003).⁵

One way of reaching prophylactic levels earlier would be to give mefloquine 250 mg daily for 3 days followed by 250 mg weekly.⁴ A safety study of 157 healthy US Marine volunteers showed that preloading achieves prophylactic blood levels of mefloquine by the third day while weekly mefloquine is subprophylactic until the fifth week.⁴

While a study of the long-term use of mefloquine in 421 healthy Peace Corps volunteers has shown it to be safe,⁶ clinical trials and case reports indicate that a loading dose of mefloquine is associated with adverse drug events, which include neuropsychiatric and gastrointestinal symptoms.^4,7

TABLE
Evidence-based recommendations for prevention of malaria^2-3,8

Recommendations from others

The World Health Organization (WHO) states that “weekly mefloquine should be started at least 1 week, but preferably 2–3 weeks before departure, to achieve higher pre-travel blood levels and to allow side effects to be detected before travel so that possible alternatives can be considered.”⁸

Centers for Disease Control and Prevention recommendations integrate recommendations from WHO and Cochrane.

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

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

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

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

Orbital cellulitis is a serious soft-tissue infection of childhood with very different etiologies.

• Periorbital (or preseptal) cellulitis is synonymous with stage I orbital cellulitis, in which there is induration, erythema, warmth, and tenderness of the periorbital soft tissues, usually secondary to external inoculation, but the inflammation does not extend into the bony orbit.
• Stages II, III, and IV orbital cellulitis are progressively more invasive infections that generally arise from the sinuses; they may involve the retro-orbital area. These stages of orbital cellulitis can cause proptosis, decrease visual acuity, or appear as abscesses on computed tomography scan.^1,2

Staged treatment

Many retrospective studies of stage II–IV orbital cellulitis with relatively few subjects and small prospective case series have been published with common themes for management recommendations:

• early intravenous antibiotics (likely for an inpatient), and
• involvement of otolaryngology and ophthalmology specialists.

No head-to-head trials have been completed to evaluate efficacy of specific antimicrobial regimens.

Oral antibiotics. First, treat stage I orbital cellulitis with oral antibiotics.

IV antibiotics. Modify treatment to intravenous antibiotics when there is no improvement within 24 hours or if you discover any characteristic of more severe orbital cellulitis.

Medical management of stage II–IV orbital cellulitis with intravenous antibiotics is the current standard of care until it is clear that one of the following is present:

• no improvement by 24 to 48 hours
• visual impairment
• complete ophthalmoplegia, or
• well-defined periosteal abscess.^1,2

Surgery. For refractory cases, surgical decompression will likely be required.

The evidence. A small case series (n=9) found 21 children admitted to hospital for preseptal cellulitis, of whom 4 later were diagnosed with orbital cellulitis. There was a total of 9 cases of orbital cellulitis; however, only 1 required operative management of orbital cellulitis.³ In a prospective study to evaluate medical management (n=23), 87% of patients responded to intravenous antibiotics.⁴ No statistically significant long-term difference in subperiosteal abscesses (as a complication of orbital cellulitis) was found in another retrospective study comparing medical to surgical management.⁵

Target the likely pathogens

Direct antimicrobial therapy toward common pathogens for likely sources of infection, paying attention to local resistance patterns and the pathogens usually associated with sinusitis (TABLE).^1,2,6-8

A retrospective case series of 94 patients of all ages in China implicated Staphylococcus aureus and streptococcal species based on cultures taken from eye purulence and abscesses.⁶ Another retrospective case series from Vanderbilt (n=80) found streptococci as the most common cause, based on blood and wound cultures in the Hib vaccination era; however, only 12 wounds returned positive cultures.⁷

TABLE
Choose antibiotic based on cause and likely pathogen^1,2,6-8

Steroids have no proven benefit

Systemic steroids have no proven benefit in the treatment of pediatric orbital cellulitis with subperiosteal abscess.

A small retrospective cohort study of the benefit of intravenous steroids in addition to antibiotics showed no decrease in hospital stay or need for surgical decompression (n=23, P=.26 and .20, respectively).⁹ Without prospective data and a power analysis, lack of benefit of steroids cannot be definitively shown.

Recommendations from others

Infectious Disease Society of America. The guidelines for the management of skin and soft-tissue infections implicate β-hemolytic streptococci as the most common cellulitis pathogen, but also recommend empiric coverage against S aureus.

Periorbital and orbital cellulitis are not specifically addressed in these guidelines, but oral dicloxacillin, cephalexin, clindamycin, or erythromycin are recommended for superficial cellulitis, provided there is no known resistance to these antibiotics.

Intravenous penicillinase-resistant penicillins (nafcillin) or a first-generation cephalosporin (cefazolin) may be used for more severe infections.

For penicillin-allergic patients, the IDSA recommends clindamycin or vancomycin.¹⁰

Sanford Guide to Antimicrobial Therapy. Nafcillin plus ceftriaxone and metronidazole is the recommended treatment for orbital cellulitis.

For patients allergic to penicillin, vancomycin plus levofloxacin and metronidazole are recommended.⁸

Neither the American Academy of Ophthalmology nor the International Council of Ophthalmology offers clinical statements on orbital cellulitis.

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

Acute chorioamnionitis (or intra-amniotic infection) poses a high risk of maternal and neonatal morbidity. Neonatal sepsis or pneumonia occurs in up to 24% of infants born to mothers with chorioamnionitis;¹ 1% to 2% of pregnancies complicated by chorioamnionitis end in neonatal death.^1,2

Acute chorioamnionitis is defined as intrapartum maternal fever and maternal tachycardia, fetal tachycardia, uterine tenderness, or purulent amniotic fluid.^1,3 Antibiotic treatment of acute chorioamnionitis is widely accepted, yet in vivo studies to determine the most effective empiric antibiotic regimens are lacking.

Intrapartum antibiotics probably reduce sepsis

Although few well-designed trials stand out, a Cochrane review⁴ summarizing 2 relevant studies is available. Gibbs et al³ performed an underpowered, randomized comparative trial of intrapartum vs postpartum treatment of chorioamnionitis, with both groups (45 patients total) receiving ampicillin 2 g IV every 6 hours plus gentamicin 1.5 mg/kg IV every 8 hours.³ Those women who underwent cesarean section also received clindamycin 900 mg IV every 8 hours starting at cord clamping. In this study, investigators reported neonatal sepsis was significantly reduced with intrapartum treatment (0 vs 21%; P=.03, number needed to treat=4.8), as were neonatal hospital stays (3.8 vs 5.7 days; P=.02), regardless of delivery method. The study had been planned for 92 patients; it was stopped early (n=48) after an interim analysis.

Because of the small sample size, other findings from the study must be viewed with caution. Intrapartum treatment with antibiotics was associated with a “significant” clinical reduction in neonatal sepsis (relative risk [RR]=0.08; 95% confidence interval [CI], 0.00–1.44) and pneumonia (RR=0.15; 95% CI, 0.01–2.92) compared with treatment given immediately postpartum; however, neither value was truly statistically significant according to the Cochrane review.⁴

The research suggests a potential benefit to adding clindamycin to ampicillin and gentamicin. In an effort to test this, 1 study randomized 133 women into 2 arms—treatment with ampicillin, gentamicin, and clindamycin compared with ampicillin and gentamicin alone—and found no additional benefit in regards to neonatal sepsis (RR=2.16; 95% CI, 0.20–23.21) or neonatal death (RR=0.72; 95% CI, 0.12–4.16).¹ There was a trend towards a decrease in the incidence of postpartum endometritis in women who received ampicillin, gentamicin, and clindamycin, but this did not reach statistical significance (RR=0.54; 95% CI, 0.19–1.49).⁴

Recommendations from others

A 2002 bulletin from American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics⁵ recommended the combination of ampicillin 2 gm IV every 4 to 6 hours or penicillin 5 million units IV every 4 to 6 hours, plus an aminoglycoside (such as gentamicin 1.5 mg/kg IV every 8 hours), since this regimen provides appropriate coverage for typical organisms associated with acute chorioamnionitis. At the time the bulletin was published, the use of single daily dosing of aminoglycoside did not have sufficient studies to back its use. In addition, ACOG recommends adding clindamycin, metronidazole, or an extended-spectrum third-generation cephalosporin to the treatment regimen if cesarean section is required, to provide coverage for anaerobic organisms. They recommend clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. The Nottingham Guideline Development Group recommends amoxicillin 2 gm IV initially then 1 gm every 8 hours, and in place of gentamicin, recommends metronidazole 500 mg IV, every 8 hours (or 1 gm PR twice a day).⁶ Both recommendations suggest clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. For patients with nonanaphylactic reactions to penicillin, they recommend cefotaxime 1 g IV every 8 hours.

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

Acute chorioamnionitis (or intra-amniotic infection) poses a high risk of maternal and neonatal morbidity. Neonatal sepsis or pneumonia occurs in up to 24% of infants born to mothers with chorioamnionitis;¹ 1% to 2% of pregnancies complicated by chorioamnionitis end in neonatal death.^1,2

Acute chorioamnionitis is defined as intrapartum maternal fever and maternal tachycardia, fetal tachycardia, uterine tenderness, or purulent amniotic fluid.^1,3 Antibiotic treatment of acute chorioamnionitis is widely accepted, yet in vivo studies to determine the most effective empiric antibiotic regimens are lacking.

Intrapartum antibiotics probably reduce sepsis

Although few well-designed trials stand out, a Cochrane review⁴ summarizing 2 relevant studies is available. Gibbs et al³ performed an underpowered, randomized comparative trial of intrapartum vs postpartum treatment of chorioamnionitis, with both groups (45 patients total) receiving ampicillin 2 g IV every 6 hours plus gentamicin 1.5 mg/kg IV every 8 hours.³ Those women who underwent cesarean section also received clindamycin 900 mg IV every 8 hours starting at cord clamping. In this study, investigators reported neonatal sepsis was significantly reduced with intrapartum treatment (0 vs 21%; P=.03, number needed to treat=4.8), as were neonatal hospital stays (3.8 vs 5.7 days; P=.02), regardless of delivery method. The study had been planned for 92 patients; it was stopped early (n=48) after an interim analysis.

Because of the small sample size, other findings from the study must be viewed with caution. Intrapartum treatment with antibiotics was associated with a “significant” clinical reduction in neonatal sepsis (relative risk [RR]=0.08; 95% confidence interval [CI], 0.00–1.44) and pneumonia (RR=0.15; 95% CI, 0.01–2.92) compared with treatment given immediately postpartum; however, neither value was truly statistically significant according to the Cochrane review.⁴

The research suggests a potential benefit to adding clindamycin to ampicillin and gentamicin. In an effort to test this, 1 study randomized 133 women into 2 arms—treatment with ampicillin, gentamicin, and clindamycin compared with ampicillin and gentamicin alone—and found no additional benefit in regards to neonatal sepsis (RR=2.16; 95% CI, 0.20–23.21) or neonatal death (RR=0.72; 95% CI, 0.12–4.16).¹ There was a trend towards a decrease in the incidence of postpartum endometritis in women who received ampicillin, gentamicin, and clindamycin, but this did not reach statistical significance (RR=0.54; 95% CI, 0.19–1.49).⁴

Recommendations from others

A 2002 bulletin from American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics⁵ recommended the combination of ampicillin 2 gm IV every 4 to 6 hours or penicillin 5 million units IV every 4 to 6 hours, plus an aminoglycoside (such as gentamicin 1.5 mg/kg IV every 8 hours), since this regimen provides appropriate coverage for typical organisms associated with acute chorioamnionitis. At the time the bulletin was published, the use of single daily dosing of aminoglycoside did not have sufficient studies to back its use. In addition, ACOG recommends adding clindamycin, metronidazole, or an extended-spectrum third-generation cephalosporin to the treatment regimen if cesarean section is required, to provide coverage for anaerobic organisms. They recommend clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. The Nottingham Guideline Development Group recommends amoxicillin 2 gm IV initially then 1 gm every 8 hours, and in place of gentamicin, recommends metronidazole 500 mg IV, every 8 hours (or 1 gm PR twice a day).⁶ Both recommendations suggest clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. For patients with nonanaphylactic reactions to penicillin, they recommend cefotaxime 1 g IV every 8 hours.

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

Acute chorioamnionitis (or intra-amniotic infection) poses a high risk of maternal and neonatal morbidity. Neonatal sepsis or pneumonia occurs in up to 24% of infants born to mothers with chorioamnionitis;¹ 1% to 2% of pregnancies complicated by chorioamnionitis end in neonatal death.^1,2

Acute chorioamnionitis is defined as intrapartum maternal fever and maternal tachycardia, fetal tachycardia, uterine tenderness, or purulent amniotic fluid.^1,3 Antibiotic treatment of acute chorioamnionitis is widely accepted, yet in vivo studies to determine the most effective empiric antibiotic regimens are lacking.

Intrapartum antibiotics probably reduce sepsis

Although few well-designed trials stand out, a Cochrane review⁴ summarizing 2 relevant studies is available. Gibbs et al³ performed an underpowered, randomized comparative trial of intrapartum vs postpartum treatment of chorioamnionitis, with both groups (45 patients total) receiving ampicillin 2 g IV every 6 hours plus gentamicin 1.5 mg/kg IV every 8 hours.³ Those women who underwent cesarean section also received clindamycin 900 mg IV every 8 hours starting at cord clamping. In this study, investigators reported neonatal sepsis was significantly reduced with intrapartum treatment (0 vs 21%; P=.03, number needed to treat=4.8), as were neonatal hospital stays (3.8 vs 5.7 days; P=.02), regardless of delivery method. The study had been planned for 92 patients; it was stopped early (n=48) after an interim analysis.

Because of the small sample size, other findings from the study must be viewed with caution. Intrapartum treatment with antibiotics was associated with a “significant” clinical reduction in neonatal sepsis (relative risk [RR]=0.08; 95% confidence interval [CI], 0.00–1.44) and pneumonia (RR=0.15; 95% CI, 0.01–2.92) compared with treatment given immediately postpartum; however, neither value was truly statistically significant according to the Cochrane review.⁴

The research suggests a potential benefit to adding clindamycin to ampicillin and gentamicin. In an effort to test this, 1 study randomized 133 women into 2 arms—treatment with ampicillin, gentamicin, and clindamycin compared with ampicillin and gentamicin alone—and found no additional benefit in regards to neonatal sepsis (RR=2.16; 95% CI, 0.20–23.21) or neonatal death (RR=0.72; 95% CI, 0.12–4.16).¹ There was a trend towards a decrease in the incidence of postpartum endometritis in women who received ampicillin, gentamicin, and clindamycin, but this did not reach statistical significance (RR=0.54; 95% CI, 0.19–1.49).⁴

Recommendations from others

A 2002 bulletin from American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics⁵ recommended the combination of ampicillin 2 gm IV every 4 to 6 hours or penicillin 5 million units IV every 4 to 6 hours, plus an aminoglycoside (such as gentamicin 1.5 mg/kg IV every 8 hours), since this regimen provides appropriate coverage for typical organisms associated with acute chorioamnionitis. At the time the bulletin was published, the use of single daily dosing of aminoglycoside did not have sufficient studies to back its use. In addition, ACOG recommends adding clindamycin, metronidazole, or an extended-spectrum third-generation cephalosporin to the treatment regimen if cesarean section is required, to provide coverage for anaerobic organisms. They recommend clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. The Nottingham Guideline Development Group recommends amoxicillin 2 gm IV initially then 1 gm every 8 hours, and in place of gentamicin, recommends metronidazole 500 mg IV, every 8 hours (or 1 gm PR twice a day).⁶ Both recommendations suggest clindamycin 900 mg IV every 8 hours to replace amoxicillin in penicillin-allergic patients. For patients with nonanaphylactic reactions to penicillin, they recommend cefotaxime 1 g IV every 8 hours.

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

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors 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

Low HDL is recognized as a risk factor for atherosclerosis. Clinicians find raising HDL a challenge, and patients often inquire about dietary advice that may help raise HDL.

No quality evidence exists that specifically looks at the effect of a dietary intervention on HDL or whether it affects survival. However, several dietary intervention studies in specific populations include HDL as a secondary endpoint in the study. This leaves clinicians to act on physiologic data that may or may not increase the overall health and survival of patients. Dietary interventions that raised HDL include low-carbohydrate diets, the DASH diet, supplementation with soy protein including isoflavones, and multivitamin supplementation.

TABLE
Summary of studies evaluating the effect of various diets on HDL cholesterol

Several overall diet interventions appear to raise HDL, but whether this affects cardiovascular events or mortality is unknown. A systematic review with meta-analysis of 5 randomized controlled trials (RCTs) of low-carbohydrate versus low-fat diets showed a 10% increase in HDL attributed to the low-carbohydrate diet, which translated to an absolute increase of 4.6 mg/dL (95% confidence interval [CI], 1.5–8.1).¹ A subsequent uncontrolled prospective trial was consistent with consistent with this systematic review and showed a 12% increase in HDL.² The DASH diet was studied as an intervention in a RCT of 116 patients with the metabolic syndrome. Men responded with an in crease of 21% and women with an increase of 33%.³

Supplementation with several food additives and nutritional supplements has been tested. A systematic review with meta-analysis of 23 RCTs evaluating effect of various amounts of soy protein with isoflavones on lipid profile found a 3% increase in HDL with an absolute difference 1.5 mg/dL (95% CI, 0.0–2.8).⁴ Supplementation with standard multivitamins in a single small, crossover RCT showed a 31% increase in HDL.⁵

Many other strategies, supplements, and plans have been tested in different populations. Other than the above interventions, no other interventions raise HDL when subjected to meta-analysis or quality randomized trials (TABLE).

Recommendations from others

No specific guidelines on dietary therapy of HDL exist; however, the American Heart Association (AHA) published diet and lifestyle recommendations in 2006.¹⁴ These guidelines recommend a diet low in fat, saturated fat, trans fat, and cholesterol in addition to minimizing sodium, added sugars, and alcohol. The AHA also recommends for consumption of oily fish and the DASH diet.

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

Low HDL is recognized as a risk factor for atherosclerosis. Clinicians find raising HDL a challenge, and patients often inquire about dietary advice that may help raise HDL.

No quality evidence exists that specifically looks at the effect of a dietary intervention on HDL or whether it affects survival. However, several dietary intervention studies in specific populations include HDL as a secondary endpoint in the study. This leaves clinicians to act on physiologic data that may or may not increase the overall health and survival of patients. Dietary interventions that raised HDL include low-carbohydrate diets, the DASH diet, supplementation with soy protein including isoflavones, and multivitamin supplementation.

TABLE
Summary of studies evaluating the effect of various diets on HDL cholesterol

Several overall diet interventions appear to raise HDL, but whether this affects cardiovascular events or mortality is unknown. A systematic review with meta-analysis of 5 randomized controlled trials (RCTs) of low-carbohydrate versus low-fat diets showed a 10% increase in HDL attributed to the low-carbohydrate diet, which translated to an absolute increase of 4.6 mg/dL (95% confidence interval [CI], 1.5–8.1).¹ A subsequent uncontrolled prospective trial was consistent with consistent with this systematic review and showed a 12% increase in HDL.² The DASH diet was studied as an intervention in a RCT of 116 patients with the metabolic syndrome. Men responded with an in crease of 21% and women with an increase of 33%.³

Supplementation with several food additives and nutritional supplements has been tested. A systematic review with meta-analysis of 23 RCTs evaluating effect of various amounts of soy protein with isoflavones on lipid profile found a 3% increase in HDL with an absolute difference 1.5 mg/dL (95% CI, 0.0–2.8).⁴ Supplementation with standard multivitamins in a single small, crossover RCT showed a 31% increase in HDL.⁵

Many other strategies, supplements, and plans have been tested in different populations. Other than the above interventions, no other interventions raise HDL when subjected to meta-analysis or quality randomized trials (TABLE).

Recommendations from others

No specific guidelines on dietary therapy of HDL exist; however, the American Heart Association (AHA) published diet and lifestyle recommendations in 2006.¹⁴ These guidelines recommend a diet low in fat, saturated fat, trans fat, and cholesterol in addition to minimizing sodium, added sugars, and alcohol. The AHA also recommends for consumption of oily fish and the DASH diet.

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

Low HDL is recognized as a risk factor for atherosclerosis. Clinicians find raising HDL a challenge, and patients often inquire about dietary advice that may help raise HDL.

No quality evidence exists that specifically looks at the effect of a dietary intervention on HDL or whether it affects survival. However, several dietary intervention studies in specific populations include HDL as a secondary endpoint in the study. This leaves clinicians to act on physiologic data that may or may not increase the overall health and survival of patients. Dietary interventions that raised HDL include low-carbohydrate diets, the DASH diet, supplementation with soy protein including isoflavones, and multivitamin supplementation.

TABLE
Summary of studies evaluating the effect of various diets on HDL cholesterol

Several overall diet interventions appear to raise HDL, but whether this affects cardiovascular events or mortality is unknown. A systematic review with meta-analysis of 5 randomized controlled trials (RCTs) of low-carbohydrate versus low-fat diets showed a 10% increase in HDL attributed to the low-carbohydrate diet, which translated to an absolute increase of 4.6 mg/dL (95% confidence interval [CI], 1.5–8.1).¹ A subsequent uncontrolled prospective trial was consistent with consistent with this systematic review and showed a 12% increase in HDL.² The DASH diet was studied as an intervention in a RCT of 116 patients with the metabolic syndrome. Men responded with an in crease of 21% and women with an increase of 33%.³

Supplementation with several food additives and nutritional supplements has been tested. A systematic review with meta-analysis of 23 RCTs evaluating effect of various amounts of soy protein with isoflavones on lipid profile found a 3% increase in HDL with an absolute difference 1.5 mg/dL (95% CI, 0.0–2.8).⁴ Supplementation with standard multivitamins in a single small, crossover RCT showed a 31% increase in HDL.⁵

Many other strategies, supplements, and plans have been tested in different populations. Other than the above interventions, no other interventions raise HDL when subjected to meta-analysis or quality randomized trials (TABLE).

Recommendations from others

No specific guidelines on dietary therapy of HDL exist; however, the American Heart Association (AHA) published diet and lifestyle recommendations in 2006.¹⁴ These guidelines recommend a diet low in fat, saturated fat, trans fat, and cholesterol in addition to minimizing sodium, added sugars, and alcohol. The AHA also recommends for consumption of oily fish and the DASH diet.

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

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

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

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

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

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force medical department 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

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.