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What are the indications for meningococcal vaccination?
Routine vaccination with the meningococcal conjugate vaccine MCV4 (Menactra) is indicated for all US adolescents entering high school and for college freshmen living in dormitories (strength of recommendation [SOR]: B, based on observational studies). For convenience, MCV4 can be given at the 11- to 12-year-old visit.
High-risk individuals (ages 2 and older) who should receive meningococcal vaccine (MCV4 or the unconjugated polysaccharide vaccine [MPSV4]) include those with terminal complement deficiencies, asplenia, or HIV, as well as military recruits, laboratory personnel exposed to aerosolized meningococci, and travelers to areas hyperendemic or epidemic for Neisseria meningitides (SOR: C, based on consensus guidelines). Routine vaccination of infants and toddlers with conjugate vaccine may be more cost-effective than targeting adolescents, but conjugate meningococcal vaccine for this age group is not yet available in the US (SOR: B, based on cohort studies).
The vaccine is available and efficacious—use it well
Mark Stephens, MD
Uniformed Services University, Bethesda, Md
As a junior military medical officer, my first assignment was in San Diego, California near the former Naval Training Center (NTC). The NTC was the site of one of the last major outbreaks of meningococcal disease in a military barracks setting. I recall with alacrity the rapidity with which this disease overcomes its host, and the overwhelming morbidity (and mortality) the disease leaves behind if treatment is delayed. This is truly a “not-to-be-missed” diagnosis.
The historical parallels between smallpox and meningococcal disease are striking. Each is spread primarily by respiratory means, particularly in close quarters. While meningococcal disease is amenable to antibiotic treatment when recognized early (contrary to smallpox), the principles of high-risk “herd” immunization hold true for both conditions. By focusing on high-risk groups and adhering to ACIP recommendations, control of meningococcal disease is within the grasp of modern medical science. The vaccine is available. The vaccine is efficacious. Use it well.
Evidence summary
Two meningococcal vaccines are currently available in the US: tetravalent polysaccharide vaccine (MPSV4) and tetravalent polysaccharide-protein conjugate vaccine (MCV4). Both protect against serogroups A, C, Y, and W-135, but not against serogroup B, which is the most prevalent. A vaccine for serogroup B is under development.
MPSV4 is licensed for ages 2 years and up, but its poor immunogenicity in infants, lack of memory and booster response, and relatively short duration of protection have restricted its use. MCV4 is licensed for 11- to 55-year-olds and is the preferred vaccine in this age group, since it provides longer duration of immunity and reduces nasopharyngeal carriage.1
Infants and freshman are especially vulnerable
Using active community surveillance from 1991 to 2002, Centers for Disease Control and Prevention (CDC) data2 found annual rates of meningococcal disease in the US of 0.5 to 1.1 per 100,000. The highest rates were found in children under age 2. Infants younger than 12 months of age were especially vulnerable (rate 9/100,000), with more than 50% of cases caused by serogroup B.
A 1998–1999 prospective surveillance study3 including 50 state health departments and 231 college health centers identified 96 cases of meningococcal disease in college students (incidence 0.7/100,000). Freshmen living in dormitories had an elevated risk of meningococcal disease compared with other undergraduates or nonstudents of the same age (incidence 5.1/100,000; adjusted relative risk=3.6 [95% confidence interval [CI], 1.6–8.5). Sixty-eight percent had illness due to a vaccine-preventable serogroup.
Using CDC incidence data, a cost-effectiveness model4 compared hypothetical vaccination strategies targeting US infants (3 doses), toddlers (1 dose), or 11-year-olds (1 dose). Routine MCV4 vaccination of all 11-year-olds would prevent 270 cases and 36 deaths in this cohort over their next 22 years. For a toddler cohort, vaccination would prevent 385 cases and 33 deaths; for infants, 447 cases and 36 deaths. Conjugate meningococcal vaccines for serogroups A and C have been tested and used in children in other countries, and appear safe and effective, but are not yet available in the US. An application has been submitted for FDA approval of MCV4 for 2- to 10-year-olds.
Herd immunity may expand benefit of vaccination
A British study compared attack rates for meningococcal C disease in children from infancy to age 18 before and 1 to 2 years after the institution of a nationwide meningococcal serogroup C conjugate vaccination. Vaccine coverage ranged from 66% (adolescents) to 87% (schoolchildren), and vaccine efficacy was 94% to 96%. Incidence of meningococcal C disease in the unvaccinated children also decreased by 52% to 67% (from 4.08/100,000 to 1.36/100,000).5
Vaccinating adolescents may be particularly helpful for building herd immunity. A Norwegian study of nasopharyngeal meningococcal carriage among 943 unimmunized individuals ages 2 months to 95 years found a carriage rate of 28% among 15- to 24-year-olds, compared with 9.6% overall.6
High hospitalization rates in US military recruits during 1964 to 1970 (25.2/100,000) led to the development of the meningococcal polysaccharide vaccine. Since 1971, all new military recruits have received polysaccharide meningococcal vaccine, and for the period 1990 to 1998 the hospitalization rate for meningococcal disease among active duty service members had decreased by 98% (to 0.51/100,000).7
Recommendations from others
The Advisory Committee on Immunization Practices,2 American Academy of Pediatrics,8 American Academy of Family Physicians,9 and American College Association10 recommendations are summarized in the TABLE. Recommendations for vaccination during meningococcal disease outbreaks can be found at www.cdc.gov.2
TABLE
Who should get vaccinated—and when
| TARGET POPULATION | VACCINE TYPE |
|---|---|
| Children 2–10 years at increased risk* | MPSV4† |
| Adolescents 11–12 years | MCV4 |
| Adolescents at high school entry or 15 years of age without prior vaccination | MCV4 |
| College freshmen planning to reside in dormitories | MCV4‡ |
| Patients ages 11–55 at increased risk* | MCV4‡ |
| Patients older than 55 years at increased risk* | MPSV4 |
| Microbiologist, lab personnel exposed to N meningitides | MCV4‡ |
| Military recruits | MCV4‡ |
| *“Increased risk” is defined by terminal complement deficiency, anatomic or functional asplenia, travel to endemic areas, HIV infection (optional). | |
| †May be repeated every 3 to 5 years if increased risk continues. | |
| ‡MPSV4 is an acceptable alternative. | |
| MPSV4, meningococcal polysaccharide vaccine; MCV4, meningococcal polysaccharide diphtheria toxoid conjugate vaccine. | |
| Adapted from Harrison, Clinical Microbiology Reviews 2006;1 Kimmel, Am Fam Physician 2005.9 | |
1. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006;19:142-164.
2. Bilukha OO, Rosenstein N. National Center for Infectious Diseases; Center for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-21. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm. Accessed on April 19, 2007.
3. Bruce MG, Rosenstein NE, Capparella JM, et al. Risk factors for meningococcal disease in college students. JAMA 2001;286:688-693.
4. Shepard CW, Ortega-Sanchez IR, Scott II RD, Rosenstein NE, ABCs Team. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics 2005;115:1220-1232.
5. Ramsay ME, Andrews NJ, Trotter CL, et al. Herd immunity from meningococcal serogroup C conjugate vaccination in England: data analysis. Br Med J 2003;326:365-366.
6. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population. J Clin Microbiology 1994;32:323-330.
7. US Department of Health and Human Services. Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000;49(RR-07):11-20.
8. American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics 2005;116:496-505.
9. Kimmel SR. Prevention of meningococcal disease. Am Fam Physician 2005;72:2049-2056.
10. American College Health Association. ACHA guidelines: recommendations for institutional prematriculation immunizations, 2006. Available at www.acha.org/info_resources/RIPIstatement.pdf. Accessed on April 3, 2007.
Routine vaccination with the meningococcal conjugate vaccine MCV4 (Menactra) is indicated for all US adolescents entering high school and for college freshmen living in dormitories (strength of recommendation [SOR]: B, based on observational studies). For convenience, MCV4 can be given at the 11- to 12-year-old visit.
High-risk individuals (ages 2 and older) who should receive meningococcal vaccine (MCV4 or the unconjugated polysaccharide vaccine [MPSV4]) include those with terminal complement deficiencies, asplenia, or HIV, as well as military recruits, laboratory personnel exposed to aerosolized meningococci, and travelers to areas hyperendemic or epidemic for Neisseria meningitides (SOR: C, based on consensus guidelines). Routine vaccination of infants and toddlers with conjugate vaccine may be more cost-effective than targeting adolescents, but conjugate meningococcal vaccine for this age group is not yet available in the US (SOR: B, based on cohort studies).
The vaccine is available and efficacious—use it well
Mark Stephens, MD
Uniformed Services University, Bethesda, Md
As a junior military medical officer, my first assignment was in San Diego, California near the former Naval Training Center (NTC). The NTC was the site of one of the last major outbreaks of meningococcal disease in a military barracks setting. I recall with alacrity the rapidity with which this disease overcomes its host, and the overwhelming morbidity (and mortality) the disease leaves behind if treatment is delayed. This is truly a “not-to-be-missed” diagnosis.
The historical parallels between smallpox and meningococcal disease are striking. Each is spread primarily by respiratory means, particularly in close quarters. While meningococcal disease is amenable to antibiotic treatment when recognized early (contrary to smallpox), the principles of high-risk “herd” immunization hold true for both conditions. By focusing on high-risk groups and adhering to ACIP recommendations, control of meningococcal disease is within the grasp of modern medical science. The vaccine is available. The vaccine is efficacious. Use it well.
Evidence summary
Two meningococcal vaccines are currently available in the US: tetravalent polysaccharide vaccine (MPSV4) and tetravalent polysaccharide-protein conjugate vaccine (MCV4). Both protect against serogroups A, C, Y, and W-135, but not against serogroup B, which is the most prevalent. A vaccine for serogroup B is under development.
MPSV4 is licensed for ages 2 years and up, but its poor immunogenicity in infants, lack of memory and booster response, and relatively short duration of protection have restricted its use. MCV4 is licensed for 11- to 55-year-olds and is the preferred vaccine in this age group, since it provides longer duration of immunity and reduces nasopharyngeal carriage.1
Infants and freshman are especially vulnerable
Using active community surveillance from 1991 to 2002, Centers for Disease Control and Prevention (CDC) data2 found annual rates of meningococcal disease in the US of 0.5 to 1.1 per 100,000. The highest rates were found in children under age 2. Infants younger than 12 months of age were especially vulnerable (rate 9/100,000), with more than 50% of cases caused by serogroup B.
A 1998–1999 prospective surveillance study3 including 50 state health departments and 231 college health centers identified 96 cases of meningococcal disease in college students (incidence 0.7/100,000). Freshmen living in dormitories had an elevated risk of meningococcal disease compared with other undergraduates or nonstudents of the same age (incidence 5.1/100,000; adjusted relative risk=3.6 [95% confidence interval [CI], 1.6–8.5). Sixty-eight percent had illness due to a vaccine-preventable serogroup.
Using CDC incidence data, a cost-effectiveness model4 compared hypothetical vaccination strategies targeting US infants (3 doses), toddlers (1 dose), or 11-year-olds (1 dose). Routine MCV4 vaccination of all 11-year-olds would prevent 270 cases and 36 deaths in this cohort over their next 22 years. For a toddler cohort, vaccination would prevent 385 cases and 33 deaths; for infants, 447 cases and 36 deaths. Conjugate meningococcal vaccines for serogroups A and C have been tested and used in children in other countries, and appear safe and effective, but are not yet available in the US. An application has been submitted for FDA approval of MCV4 for 2- to 10-year-olds.
Herd immunity may expand benefit of vaccination
A British study compared attack rates for meningococcal C disease in children from infancy to age 18 before and 1 to 2 years after the institution of a nationwide meningococcal serogroup C conjugate vaccination. Vaccine coverage ranged from 66% (adolescents) to 87% (schoolchildren), and vaccine efficacy was 94% to 96%. Incidence of meningococcal C disease in the unvaccinated children also decreased by 52% to 67% (from 4.08/100,000 to 1.36/100,000).5
Vaccinating adolescents may be particularly helpful for building herd immunity. A Norwegian study of nasopharyngeal meningococcal carriage among 943 unimmunized individuals ages 2 months to 95 years found a carriage rate of 28% among 15- to 24-year-olds, compared with 9.6% overall.6
High hospitalization rates in US military recruits during 1964 to 1970 (25.2/100,000) led to the development of the meningococcal polysaccharide vaccine. Since 1971, all new military recruits have received polysaccharide meningococcal vaccine, and for the period 1990 to 1998 the hospitalization rate for meningococcal disease among active duty service members had decreased by 98% (to 0.51/100,000).7
Recommendations from others
The Advisory Committee on Immunization Practices,2 American Academy of Pediatrics,8 American Academy of Family Physicians,9 and American College Association10 recommendations are summarized in the TABLE. Recommendations for vaccination during meningococcal disease outbreaks can be found at www.cdc.gov.2
TABLE
Who should get vaccinated—and when
| TARGET POPULATION | VACCINE TYPE |
|---|---|
| Children 2–10 years at increased risk* | MPSV4† |
| Adolescents 11–12 years | MCV4 |
| Adolescents at high school entry or 15 years of age without prior vaccination | MCV4 |
| College freshmen planning to reside in dormitories | MCV4‡ |
| Patients ages 11–55 at increased risk* | MCV4‡ |
| Patients older than 55 years at increased risk* | MPSV4 |
| Microbiologist, lab personnel exposed to N meningitides | MCV4‡ |
| Military recruits | MCV4‡ |
| *“Increased risk” is defined by terminal complement deficiency, anatomic or functional asplenia, travel to endemic areas, HIV infection (optional). | |
| †May be repeated every 3 to 5 years if increased risk continues. | |
| ‡MPSV4 is an acceptable alternative. | |
| MPSV4, meningococcal polysaccharide vaccine; MCV4, meningococcal polysaccharide diphtheria toxoid conjugate vaccine. | |
| Adapted from Harrison, Clinical Microbiology Reviews 2006;1 Kimmel, Am Fam Physician 2005.9 | |
Routine vaccination with the meningococcal conjugate vaccine MCV4 (Menactra) is indicated for all US adolescents entering high school and for college freshmen living in dormitories (strength of recommendation [SOR]: B, based on observational studies). For convenience, MCV4 can be given at the 11- to 12-year-old visit.
High-risk individuals (ages 2 and older) who should receive meningococcal vaccine (MCV4 or the unconjugated polysaccharide vaccine [MPSV4]) include those with terminal complement deficiencies, asplenia, or HIV, as well as military recruits, laboratory personnel exposed to aerosolized meningococci, and travelers to areas hyperendemic or epidemic for Neisseria meningitides (SOR: C, based on consensus guidelines). Routine vaccination of infants and toddlers with conjugate vaccine may be more cost-effective than targeting adolescents, but conjugate meningococcal vaccine for this age group is not yet available in the US (SOR: B, based on cohort studies).
The vaccine is available and efficacious—use it well
Mark Stephens, MD
Uniformed Services University, Bethesda, Md
As a junior military medical officer, my first assignment was in San Diego, California near the former Naval Training Center (NTC). The NTC was the site of one of the last major outbreaks of meningococcal disease in a military barracks setting. I recall with alacrity the rapidity with which this disease overcomes its host, and the overwhelming morbidity (and mortality) the disease leaves behind if treatment is delayed. This is truly a “not-to-be-missed” diagnosis.
The historical parallels between smallpox and meningococcal disease are striking. Each is spread primarily by respiratory means, particularly in close quarters. While meningococcal disease is amenable to antibiotic treatment when recognized early (contrary to smallpox), the principles of high-risk “herd” immunization hold true for both conditions. By focusing on high-risk groups and adhering to ACIP recommendations, control of meningococcal disease is within the grasp of modern medical science. The vaccine is available. The vaccine is efficacious. Use it well.
Evidence summary
Two meningococcal vaccines are currently available in the US: tetravalent polysaccharide vaccine (MPSV4) and tetravalent polysaccharide-protein conjugate vaccine (MCV4). Both protect against serogroups A, C, Y, and W-135, but not against serogroup B, which is the most prevalent. A vaccine for serogroup B is under development.
MPSV4 is licensed for ages 2 years and up, but its poor immunogenicity in infants, lack of memory and booster response, and relatively short duration of protection have restricted its use. MCV4 is licensed for 11- to 55-year-olds and is the preferred vaccine in this age group, since it provides longer duration of immunity and reduces nasopharyngeal carriage.1
Infants and freshman are especially vulnerable
Using active community surveillance from 1991 to 2002, Centers for Disease Control and Prevention (CDC) data2 found annual rates of meningococcal disease in the US of 0.5 to 1.1 per 100,000. The highest rates were found in children under age 2. Infants younger than 12 months of age were especially vulnerable (rate 9/100,000), with more than 50% of cases caused by serogroup B.
A 1998–1999 prospective surveillance study3 including 50 state health departments and 231 college health centers identified 96 cases of meningococcal disease in college students (incidence 0.7/100,000). Freshmen living in dormitories had an elevated risk of meningococcal disease compared with other undergraduates or nonstudents of the same age (incidence 5.1/100,000; adjusted relative risk=3.6 [95% confidence interval [CI], 1.6–8.5). Sixty-eight percent had illness due to a vaccine-preventable serogroup.
Using CDC incidence data, a cost-effectiveness model4 compared hypothetical vaccination strategies targeting US infants (3 doses), toddlers (1 dose), or 11-year-olds (1 dose). Routine MCV4 vaccination of all 11-year-olds would prevent 270 cases and 36 deaths in this cohort over their next 22 years. For a toddler cohort, vaccination would prevent 385 cases and 33 deaths; for infants, 447 cases and 36 deaths. Conjugate meningococcal vaccines for serogroups A and C have been tested and used in children in other countries, and appear safe and effective, but are not yet available in the US. An application has been submitted for FDA approval of MCV4 for 2- to 10-year-olds.
Herd immunity may expand benefit of vaccination
A British study compared attack rates for meningococcal C disease in children from infancy to age 18 before and 1 to 2 years after the institution of a nationwide meningococcal serogroup C conjugate vaccination. Vaccine coverage ranged from 66% (adolescents) to 87% (schoolchildren), and vaccine efficacy was 94% to 96%. Incidence of meningococcal C disease in the unvaccinated children also decreased by 52% to 67% (from 4.08/100,000 to 1.36/100,000).5
Vaccinating adolescents may be particularly helpful for building herd immunity. A Norwegian study of nasopharyngeal meningococcal carriage among 943 unimmunized individuals ages 2 months to 95 years found a carriage rate of 28% among 15- to 24-year-olds, compared with 9.6% overall.6
High hospitalization rates in US military recruits during 1964 to 1970 (25.2/100,000) led to the development of the meningococcal polysaccharide vaccine. Since 1971, all new military recruits have received polysaccharide meningococcal vaccine, and for the period 1990 to 1998 the hospitalization rate for meningococcal disease among active duty service members had decreased by 98% (to 0.51/100,000).7
Recommendations from others
The Advisory Committee on Immunization Practices,2 American Academy of Pediatrics,8 American Academy of Family Physicians,9 and American College Association10 recommendations are summarized in the TABLE. Recommendations for vaccination during meningococcal disease outbreaks can be found at www.cdc.gov.2
TABLE
Who should get vaccinated—and when
| TARGET POPULATION | VACCINE TYPE |
|---|---|
| Children 2–10 years at increased risk* | MPSV4† |
| Adolescents 11–12 years | MCV4 |
| Adolescents at high school entry or 15 years of age without prior vaccination | MCV4 |
| College freshmen planning to reside in dormitories | MCV4‡ |
| Patients ages 11–55 at increased risk* | MCV4‡ |
| Patients older than 55 years at increased risk* | MPSV4 |
| Microbiologist, lab personnel exposed to N meningitides | MCV4‡ |
| Military recruits | MCV4‡ |
| *“Increased risk” is defined by terminal complement deficiency, anatomic or functional asplenia, travel to endemic areas, HIV infection (optional). | |
| †May be repeated every 3 to 5 years if increased risk continues. | |
| ‡MPSV4 is an acceptable alternative. | |
| MPSV4, meningococcal polysaccharide vaccine; MCV4, meningococcal polysaccharide diphtheria toxoid conjugate vaccine. | |
| Adapted from Harrison, Clinical Microbiology Reviews 2006;1 Kimmel, Am Fam Physician 2005.9 | |
1. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006;19:142-164.
2. Bilukha OO, Rosenstein N. National Center for Infectious Diseases; Center for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-21. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm. Accessed on April 19, 2007.
3. Bruce MG, Rosenstein NE, Capparella JM, et al. Risk factors for meningococcal disease in college students. JAMA 2001;286:688-693.
4. Shepard CW, Ortega-Sanchez IR, Scott II RD, Rosenstein NE, ABCs Team. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics 2005;115:1220-1232.
5. Ramsay ME, Andrews NJ, Trotter CL, et al. Herd immunity from meningococcal serogroup C conjugate vaccination in England: data analysis. Br Med J 2003;326:365-366.
6. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population. J Clin Microbiology 1994;32:323-330.
7. US Department of Health and Human Services. Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000;49(RR-07):11-20.
8. American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics 2005;116:496-505.
9. Kimmel SR. Prevention of meningococcal disease. Am Fam Physician 2005;72:2049-2056.
10. American College Health Association. ACHA guidelines: recommendations for institutional prematriculation immunizations, 2006. Available at www.acha.org/info_resources/RIPIstatement.pdf. Accessed on April 3, 2007.
1. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006;19:142-164.
2. Bilukha OO, Rosenstein N. National Center for Infectious Diseases; Center for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-21. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm. Accessed on April 19, 2007.
3. Bruce MG, Rosenstein NE, Capparella JM, et al. Risk factors for meningococcal disease in college students. JAMA 2001;286:688-693.
4. Shepard CW, Ortega-Sanchez IR, Scott II RD, Rosenstein NE, ABCs Team. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics 2005;115:1220-1232.
5. Ramsay ME, Andrews NJ, Trotter CL, et al. Herd immunity from meningococcal serogroup C conjugate vaccination in England: data analysis. Br Med J 2003;326:365-366.
6. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population. J Clin Microbiology 1994;32:323-330.
7. US Department of Health and Human Services. Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000;49(RR-07):11-20.
8. American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics 2005;116:496-505.
9. Kimmel SR. Prevention of meningococcal disease. Am Fam Physician 2005;72:2049-2056.
10. American College Health Association. ACHA guidelines: recommendations for institutional prematriculation immunizations, 2006. Available at www.acha.org/info_resources/RIPIstatement.pdf. Accessed on April 3, 2007.
Evidence-based answers from the Family Physicians Inquiries Network
What is the preferred treatment for a child with mild persistent asthma?
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Evidence-based answers from the Family Physicians Inquiries Network
What precautions should we use with statins for women of childbearing age?
Statins are contraindicated for women who are pregnant or breastfeeding. Data evaluating statin use for women of childbearing age is limited; however, they may be used cautiously with adequate contraception. Pravastatin may be preferred based on its low tissue-penetration properties. Cholesterol-lowering with simvastatin 40 mg/d did not disrupt menstrual cycles or effect luteal phase duration (strength of recommendation: C).
Use statins only as a last resort for women of childbearing age
Ariel Smits, MD
Department of Family Medicine, Oregon Health & Science University, Portland
I try to follow the USPSTF recommendations and not screen women aged <45 years without coronary artery disease risk factors for hyperlipidemia. When a woman of any age needs treatment, my first-line therapy is lifestyle modification. Given the risks of statin drugs to the developing fetus, women with childbearing potential should give fully informed consent and be offered reliable contraception before stating statin therapy.
Before reading this review, I had not been aware of the serious effects of statin medications on the developing fetus. In conversations with my colleagues, I found that the adverse effects of statins during pregnancy are not readily known. Such information needs to be more widely disseminated.
Evidence summary
Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.1
Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.2 To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).3 These congenital anomaly frequencies do not exceed general population rates.
One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.4
Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.5
Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.2 Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.3
Recommendations from others
The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.8
The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.9 The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).
1. Moore TH, Bartlett C, Burke MA, Davey Smith G, Ebrahim SB. Statins for preventing cardiovascular disease. Cochrane Database Syst Rev 2004;(2):CD004816.
2. Draft summary of reproductive toxicology studies on Mevacor NDA 21-213: Joint Meeting of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee of the Federal Drug Administration, Merck & Co (July 13, 2000). Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3622b1b_summary.pdf. Accessed on December 7, 2005.
3. Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004;131:287-298.
4. Plotkin D, Miller S, Nakajima S, et al. Lowering low density lipoprotein cholesterol with simvastatin, a hydroxyl-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women. J Clin Endocrinol Metabol 2002;87:3155-3161.
5. Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291:2243-2252.
6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
7. Mosca L, Appel JA, Benjamin EJ, et al. AHA guidelines: Evidence-based Guidelines for Cardiovascular Disease Prevention in Women. Circulation 2004;109:672-693.
8. Herbert WNP, Braly PS, Barss VA, et al. ACOG: Guidelines for Women’s Health Care. 2nd ed. Washington, DC: ACOG; 2002;209-211.
9. US Preventive Services Task Force. Screening for lipid disorder in adults: recommendations and rationale. Internet J Intern Med 2002;3(2).-Available at: www.ispub.com/ostia/index.php?xmlFilePath=journals/ijim/vol3n2/lipid.xml. Accessed on December 8, 2005.
Statins are contraindicated for women who are pregnant or breastfeeding. Data evaluating statin use for women of childbearing age is limited; however, they may be used cautiously with adequate contraception. Pravastatin may be preferred based on its low tissue-penetration properties. Cholesterol-lowering with simvastatin 40 mg/d did not disrupt menstrual cycles or effect luteal phase duration (strength of recommendation: C).
Use statins only as a last resort for women of childbearing age
Ariel Smits, MD
Department of Family Medicine, Oregon Health & Science University, Portland
I try to follow the USPSTF recommendations and not screen women aged <45 years without coronary artery disease risk factors for hyperlipidemia. When a woman of any age needs treatment, my first-line therapy is lifestyle modification. Given the risks of statin drugs to the developing fetus, women with childbearing potential should give fully informed consent and be offered reliable contraception before stating statin therapy.
Before reading this review, I had not been aware of the serious effects of statin medications on the developing fetus. In conversations with my colleagues, I found that the adverse effects of statins during pregnancy are not readily known. Such information needs to be more widely disseminated.
Evidence summary
Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.1
Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.2 To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).3 These congenital anomaly frequencies do not exceed general population rates.
One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.4
Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.5
Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.2 Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.3
Recommendations from others
The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.8
The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.9 The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).
Statins are contraindicated for women who are pregnant or breastfeeding. Data evaluating statin use for women of childbearing age is limited; however, they may be used cautiously with adequate contraception. Pravastatin may be preferred based on its low tissue-penetration properties. Cholesterol-lowering with simvastatin 40 mg/d did not disrupt menstrual cycles or effect luteal phase duration (strength of recommendation: C).
Use statins only as a last resort for women of childbearing age
Ariel Smits, MD
Department of Family Medicine, Oregon Health & Science University, Portland
I try to follow the USPSTF recommendations and not screen women aged <45 years without coronary artery disease risk factors for hyperlipidemia. When a woman of any age needs treatment, my first-line therapy is lifestyle modification. Given the risks of statin drugs to the developing fetus, women with childbearing potential should give fully informed consent and be offered reliable contraception before stating statin therapy.
Before reading this review, I had not been aware of the serious effects of statin medications on the developing fetus. In conversations with my colleagues, I found that the adverse effects of statins during pregnancy are not readily known. Such information needs to be more widely disseminated.
Evidence summary
Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.1
Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.2 To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).3 These congenital anomaly frequencies do not exceed general population rates.
One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.4
Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.5
Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.2 Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.3
Recommendations from others
The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.8
The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.9 The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).
1. Moore TH, Bartlett C, Burke MA, Davey Smith G, Ebrahim SB. Statins for preventing cardiovascular disease. Cochrane Database Syst Rev 2004;(2):CD004816.
2. Draft summary of reproductive toxicology studies on Mevacor NDA 21-213: Joint Meeting of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee of the Federal Drug Administration, Merck & Co (July 13, 2000). Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3622b1b_summary.pdf. Accessed on December 7, 2005.
3. Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004;131:287-298.
4. Plotkin D, Miller S, Nakajima S, et al. Lowering low density lipoprotein cholesterol with simvastatin, a hydroxyl-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women. J Clin Endocrinol Metabol 2002;87:3155-3161.
5. Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291:2243-2252.
6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
7. Mosca L, Appel JA, Benjamin EJ, et al. AHA guidelines: Evidence-based Guidelines for Cardiovascular Disease Prevention in Women. Circulation 2004;109:672-693.
8. Herbert WNP, Braly PS, Barss VA, et al. ACOG: Guidelines for Women’s Health Care. 2nd ed. Washington, DC: ACOG; 2002;209-211.
9. US Preventive Services Task Force. Screening for lipid disorder in adults: recommendations and rationale. Internet J Intern Med 2002;3(2).-Available at: www.ispub.com/ostia/index.php?xmlFilePath=journals/ijim/vol3n2/lipid.xml. Accessed on December 8, 2005.
1. Moore TH, Bartlett C, Burke MA, Davey Smith G, Ebrahim SB. Statins for preventing cardiovascular disease. Cochrane Database Syst Rev 2004;(2):CD004816.
2. Draft summary of reproductive toxicology studies on Mevacor NDA 21-213: Joint Meeting of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee of the Federal Drug Administration, Merck & Co (July 13, 2000). Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3622b1b_summary.pdf. Accessed on December 7, 2005.
3. Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004;131:287-298.
4. Plotkin D, Miller S, Nakajima S, et al. Lowering low density lipoprotein cholesterol with simvastatin, a hydroxyl-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women. J Clin Endocrinol Metabol 2002;87:3155-3161.
5. Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;291:2243-2252.
6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
7. Mosca L, Appel JA, Benjamin EJ, et al. AHA guidelines: Evidence-based Guidelines for Cardiovascular Disease Prevention in Women. Circulation 2004;109:672-693.
8. Herbert WNP, Braly PS, Barss VA, et al. ACOG: Guidelines for Women’s Health Care. 2nd ed. Washington, DC: ACOG; 2002;209-211.
9. US Preventive Services Task Force. Screening for lipid disorder in adults: recommendations and rationale. Internet J Intern Med 2002;3(2).-Available at: www.ispub.com/ostia/index.php?xmlFilePath=journals/ijim/vol3n2/lipid.xml. Accessed on December 8, 2005.
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