Jun 15, 2017 Issue
 
 

Vaccine Adverse Events: Separating Myth from Reality

 

JEANNE P. SPENCER, MD; RUTH H. TRONDSEN PAWLOWSKI, MD; and STEPHANIE THOMAS, PharmD, Conemaugh Family Medicine Residency Program, Johnstown, Pennsylvania

Am Fam Physician. 2017 Jun 15;95(12):786-794.

  Related editorial: Strategies for Addressing and Overcoming Vaccine Hesitancy.

  Patient information: See related handout on vaccinations, written by the authors of this article.

Author disclosure: No relevant financial affiliations.

Article Sections

Vaccines are one of the most successful medical advances in modern times. Most vaccine-preventable illnesses are unfamiliar to modern parents. Because of this, parents are increasingly questioning the necessity of immunizing their children, especially because no vaccine is completely free of adverse effects or the risk of complications. Family physicians should be aware of the risks and benefits of recommended immunizations. Thimerosal is currently used only in multidose vials of influenza vaccine, and exposure through vaccines is not associated with adverse neurologic outcomes. The measles, mumps, and rubella vaccine is not associated with autism. Vaccines are associated with local reactions, such as pain and erythema. The rotavirus vaccine minimally increases the rate of intussusception, whereas other vaccines minimally increase the risk of syncope. Although immunization with the human papillomavirus vaccine is recommended for all boys and girls, vaccination rates remain low. Physicians should guide parents to credible resources if they are considering vaccine refusal. If a recommended vaccine is refused, proper documentation is essential. The Vaccine Adverse Event Reporting System and National Vaccine Injury Compensation Program track adverse events and allow compensation for documented harms from vaccinations.

With the success of vaccinations, many parents no longer have contact with children who have vaccine-preventable illnesses. Because of this, parents have difficulty balancing the potential harms and benefits of vaccines. Some parents express concern that physicians are not well educated on the adverse effects of vaccines or that physicians purposefully withhold information on adverse effects.1 Parents may seek out additional information from websites containing inaccurate information. Family physicians should gather accurate information about the harms and benefits of vaccines to advocate for vaccination and decrease the incidence of vaccine-preventable diseases.

WHAT IS NEW ON THIS TOPIC: VACCINE ADVERSE EVENTS

In 2012, the United States had its largest pertussis outbreak since 1955, including 48,277 cases and 20 pertussis-related deaths.

The most common adverse effects of the human papillomavirus vaccine are transient and similar to those of other vaccines, including mild pain and bruising at the injection site, headache, lightheadedness, and syncope.

The American Academy of Family Physicians does not support immunization exemption policies except in cases of allergic or medical contraindication.

 Enlarge     Print

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

A 25-mm needle should be used instead of a 16-mm needle to reduce the risk of adverse reactions to vaccinations.

A

3

Antipyretics are not recommended for routine prophylaxis before immunizations.

A

6, 7

The measles, mumps, and rubella vaccine does not increase the risk of autism and should be routinely used.

C

35, 36

Parents who refuse a recommended vaccine should sign a refusal to vaccinate form.

C

7, 79, 82

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

A 25-mm needle should be used instead of a 16-mm needle to reduce the risk of adverse reactions to vaccinations.

A

3

Antipyretics are not recommended for routine prophylaxis before immunizations.

A

6, 7

The measles, mumps, and rubella vaccine does not increase the risk of autism and should be routinely used.

C

35, 36

Parents who refuse a recommended vaccine should sign a refusal to vaccinate form.

C

7, 79, 82

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Vaccine Adverse Events

Jump to section +

Common local reactions to vaccines include pain, swelling, and erythema at the injection site. Systemic reactions, including fever, irritability, drowsiness, and rash, may also occur.2 Use of a longer needle (25 mm vs. 16 mm) decreases injection site reactions.3 The fourth dose of the diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine is associated with an increased incidence of fever and injection site reactions compared with the first dose (one in four children).2 One out of 30 children reports up to seven days of swelling of the entire thigh or upper arm after the fourth or fifth dose.2 Syncope may occur—especially in adolescents—after administration of the human papillomavirus (HPV) vaccine; quadrivalent meningococcal conjugate vaccine (MCV4); or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine.4 Because of this, adolescents should be observed for 15 minutes after receiving these vaccines.2,5 Administration of acetaminophen at the time of vaccination or shortly afterward may alleviate some adverse effects, but there may be a decreased antibody response to some vaccine antigens in children who receive antipyretics.6 For this reason and because antipyretics do not prevent febrile seizures, the Centers for Disease Control and Prevention (CDC) no longer recommends routine prophylaxis before vaccination.7

Potential Allergens in Vaccines

Jump to section +

Trace amounts of antibiotics, such as neomycin, are present in varicella; measles, mumps, and rubella (MMR); and inactivated poliovirus vaccines. Therefore, these vaccines are contraindicated in patients with a history of anaphylactic reaction to these antibiotics.8,9 Gelatin is used in some live virus vaccines, such as varicella and MMR; these vaccines should not be given to patients with a history of anaphylaxis to gelatin.8 Egg allergy is not a contraindication to the MMR vaccine, even though it is derived from chick embryo fibroblast tissue culture.9 Patients with anaphylaxis to egg proteins should not receive the inactivated influenza vaccine and should receive the egg-free trivalent inactivated influenza vaccine instead.10 The CDC publishes tables detailing the inactive ingredients or excipients and other potential allergens found in vaccines.8,11 Anaphylactic reactions to vaccines occur in approximately one per 1 million doses.12 A patient who has an anaphylactic reaction to a vaccine should undergo immediate type allergy skin testing to confirm that the reaction was immunoglobulin E mediated and to determine which vaccine component was responsible. If the skin test is negative, the vaccine can be readministered under close observation with resuscitation, including epinephrine, readily available.10,12  Every effort should be made to avoid unnecessarily withholding a disease-preventing vaccine. Table 1 lists serious adverse reactions to vaccines.8,11–26

 Enlarge     Print

Table 1.

Serious Adverse Reactions to Vaccines

VaccineDocumented reactionApproximate ratePotential allergen

Diphtheria and tetanus toxoids and acellular pertussis (DTaP)

Serious allergic reaction12–14

1 per 1,000,000 doses13

Infanrix syringe contains latex11

Measles, mumps, and rubella

Immune thrombocytopenic purpura14–18

1 per 20,000 doses19,20

Contains neomycin and gelatin8

Serious allergic reaction14–19,21

< 1 per 1,000,000 doses19,22,23

Measles, mumps, rubella, and varicella

Febrile seizure14,15,17–21,24

8.5 per 10,000 doses20

Contains neomycin and gelatin8

Meningococcal

Serious allergic reaction14,25

Rare25

Menomune and Bexsero contain latex11

Rotavirus

Intussusception12,26

1 per 20,000 to 100,000 doses26

Rotarix contains latex in oral applicator of diluents11

Information from references 8, and 11 through 26.

Table 1.

Serious Adverse Reactions to Vaccines

VaccineDocumented reactionApproximate ratePotential allergen

Diphtheria and tetanus toxoids and acellular pertussis (DTaP)

Serious allergic reaction12–14

1 per 1,000,000 doses13

Infanrix syringe contains latex11

Measles, mumps, and rubella

Immune thrombocytopenic purpura14–18

1 per 20,000 doses19,20

Contains neomycin and gelatin8

Serious allergic reaction14–19,21

< 1 per 1,000,000 doses19,22,23

Measles, mumps, rubella, and varicella

Febrile seizure14,15,17–21,24

8.5 per 10,000 doses20

Contains neomycin and gelatin8

Meningococcal

Serious allergic reaction14,25

Rare25

Menomune and Bexsero contain latex11

Rotavirus

Intussusception12,26

1 per 20,000 to 100,000 doses26

Rotarix contains latex in oral applicator of diluents11

Information from references 8, and 11 through 26.

Thimerosal in Vaccines

Jump to section +

Thimerosal, a preservative containing ethyl mercury, was used to prevent bacterial and fungal contamination of vaccines beginning in the 1930s. In 1999, the U.S. Food and Drug Administration (FDA) determined that the child immunization schedule may expose infants to more mercury than recommended by the Environmental Protection Agency.27–29 There is no link between thimerosal exposure and adverse outcomes such as autism or abnormal neuropsychological functioning.30–32 Thimerosal has been removed from all routine childhood vaccines except multidose vials of influenza vaccines.33 Inactivated influenza vaccines are formulated in both multidose vials and preservative-free single-dose vials. Annual exposure to a thimerosal-containing influenza vaccine is considered safe.34

MMR Vaccine

Jump to section +

An article linking autism to the MMR vaccine was retracted for fraud, but this misinformation persists and has caused long-lasting public health consequences.35,36 Multiple studies have found no causal link between vaccination and autism, but the falsified report continues to cause parental concern.35 Physicians must acknowledge these fears and inform concerned parents about the benefits of immunization and the potential harm of vaccine refusal. Febrile seizures that occur seven to 10 days after the first dose of the MMR vaccine are uncommon, but the risk is increased when the first dose is given after the recommended age of 12 to 15 months.37,38  The risk of immune thrombocytopenic purpura is increased after both natural measles infection and for up to six weeks after MMR vaccination (Table 2).16,18,19,21–24,39–51 Infection with measles, mumps, or rubella causes more severe adverse effects than the MMR vaccine, and vaccine refusal has been linked to recent outbreaks of these infections.45

 Enlarge     Print

Table 2.

Statistics on Measles, Mumps, Rubella, and the MMR Vaccine

Disease factorMeaslesMumpsRubellaMMR vaccine

Highest number of U.S. cases

894,134 cases (1941)39

152,209 cases (1968)40

12 million cases (1964 to 1965); 57,686 cases (1969)41

—

Congenital rubella: 20,000 cases (1964 to 1965)41

Number of recent U.S. cases

189 cases (2015)42

1,057 cases (2015)43

6 cases (2015)44

None in vaccinated persons 46

Congenital rubella: 4 cases (2005 to 2011)45

Transmission route

Oral and airborne droplets

Direct contact, airborne droplets, and saliva

Oral droplets

—

Congenital rubella: transplacental

Transmission risk in susceptible household contacts

90%47

Not available because 30% to 40% of infections are subclinical40

50% of infections are subclinical

—

During first trimester, the risk of fetal infection may be as high as 90%

Congenital rubella syndrome is rare when infection occurs after 20 weeks' gestation48

Mortality risk

2 deaths per 1,000 measles cases19

None reported22

0% to 50%16

397 cases (according to the Vaccine Adverse Event Reporting System; unknown number of vaccinations)21

Congenital rubella: 35%41

Encephalitis risk

1 case per 1,000 measles cases 19

1 case per 300 to 6,000 mumps cases 22

1 case per 6,000 rubella cases16

1 case per 3 million vaccinations18

Subacute sclerosing panencephalitis risk

8.5 cases per 1 million measles cases 39

—

Rare16

0 to 0.7 cases per 1 million vaccinations39,49

Pneumonia risk

1 case per 20 measles cases (the most common cause of death from measles in young children)50

—

—

2 cases per 1 million vaccinations 49

Thrombocytopenia risk

—

—

1 case per 3,000 rubella cases16

1 case of immune thrombocytopenic purpura per 40,000 vaccinated children (risk increased in the 6 weeks following vaccination)24

Orchitis risk

—

3 to 10 cases per 100 adolescent and adult men with mumps 51

—

0.3 cases per 1 million vaccinations 22

Anaphylaxis risk

—

—

—

0.65 cases per 1 million vaccinations23

MMR = measles, mumps, and rubella.

Information from references 16, 18, 19, 21 through 24, and 39 through 51.

Table 2.

Statistics on Measles, Mumps, Rubella, and the MMR Vaccine

Disease factorMeaslesMumpsRubellaMMR vaccine

Highest number of U.S. cases

894,134 cases (1941)39

152,209 cases (1968)40

12 million cases (1964 to 1965); 57,686 cases (1969)41

—

Congenital rubella: 20,000 cases (1964 to 1965)41

Number of recent U.S. cases

189 cases (2015)42

1,057 cases (2015)43

6 cases (2015)44

None in vaccinated persons 46

Congenital rubella: 4 cases (2005 to 2011)45

Transmission route

Oral and airborne droplets

Direct contact, airborne droplets, and saliva

Oral droplets

—

Congenital rubella: transplacental

Transmission risk in susceptible household contacts

90%47

Not available because 30% to 40% of infections are subclinical40

50% of infections are subclinical

—

During first trimester, the risk of fetal infection may be as high as 90%

Congenital rubella syndrome is rare when infection occurs after 20 weeks' gestation48

Mortality risk

2 deaths per 1,000 measles cases19

None reported22

0% to 50%16

397 cases (according to the Vaccine Adverse Event Reporting System; unknown number of vaccinations)21

Congenital rubella: 35%41

Encephalitis risk

1 case per 1,000 measles cases 19

1 case per 300 to 6,000 mumps cases 22

1 case per 6,000 rubella cases16

1 case per 3 million vaccinations18

Subacute sclerosing panencephalitis risk

8.5 cases per 1 million measles cases 39

—

Rare16

0 to 0.7 cases per 1 million vaccinations39,49

Pneumonia risk

1 case per 20 measles cases (the most common cause of death from measles in young children)50

—

—

2 cases per 1 million vaccinations 49

Thrombocytopenia risk

—

—

1 case per 3,000 rubella cases16

1 case of immune thrombocytopenic purpura per 40,000 vaccinated children (risk increased in the 6 weeks following vaccination)24

Orchitis risk

—

3 to 10 cases per 100 adolescent and adult men with mumps 51

—

0.3 cases per 1 million vaccinations 22

Anaphylaxis risk

—

—

—

0.65 cases per 1 million vaccinations23

MMR = measles, mumps, and rubella.

Information from references 16, 18, 19, 21 through 24, and 39 through 51.

HPV Vaccine

Jump to section +

HPV is a sexually transmitted infection that can cause genital warts and anogenital and oropharyngeal cancers.52,53 The HPV vaccine has been recommended for all adolescents since 2011.53 However, as of 2013 only 57.3% of girls and 34.6% of boys had received at least one dose.53 HPV immunization rates are suboptimal partly because of unfounded concerns that it encourages sexual activity at a younger age and reduces other protective behaviors.52,54,55 Although hepatitis B can also be sexually transmitted, this vaccine has had near universal uptake. Despite concerns about the safety of the vaccine, the most common adverse effects are transient and similar to those of other vaccines, such as mild pain and bruising at the injection site, headache, lightheadedness, and syncope.53,56,57

Rotavirus Vaccine

Jump to section +

The first rotavirus vaccine licensed in the United States was withdrawn because of an increased incidence of intussusception. Children who have received the newer vaccines have only a slightly increased risk of intussusception compared with unvaccinated infants and a lower risk compared to those with rotavirus infection. Intussusception occurs during the time of maximum viral replication after vaccination: three to five days after immunization with the pentavalent vaccine (Rotateq) and four to six days after immunization with the monovalent vaccine (Rotarix).58 The risk of intussusception is about one event per 100,000 vaccine doses.58 Immunizing a birth cohort of 4 million children would avert 255,000 physician visits, 137,000 visits to the emergency department, and 44,000 hospitalizations, and would prevent 13 deaths.59

Meningococcal Vaccine

Jump to section +

Universal immunization with MCV4 has been recommended for adolescents since 2005. The initial dose is recommended at 11 to 12 years of age, with a booster at 16 years of age. This vaccine protects against serogroups A, C, W135, and Y. Previous concerns about an increased risk of Guillain-Barré syndrome associated with the vaccine were unfounded.60 The most common adverse effects are fever, headache, injection site erythema, and dizziness. Immunity wanes over time, even after the booster dose.60 There are now two well-tolerated serogroup B meningococcal vaccines that the FDA approved in 2015. Previous vaccines against serogroup B meningitis caused adverse effects from cross allergenicity with antigens in the human central nervous system.61 The CDC's Advisory Committee on Immunization Practices recommends routine use of these vaccines only in high-risk persons and during outbreaks because of the low prevalence of the disease.62 These two meningococcal serogroup B vaccines are not interchangeable.62

Influenza Vaccine and Guillain-Barré Syndrome

Jump to section +

The 1976 swine influenza vaccine was associated with a four- to eightfold increased risk of Guillain-Barré syndrome, or an attributable risk of one case per 100,000 persons vaccinated.57,63 A study of the 2009 influenza vaccine did not show a similar association.64 Although the literature is conflicting, the influenza vaccine may at worst slightly increase the risk of Guillain-Barré syndrome: one hospital admission per 1 million vaccinations, or one additional case per 1.25 million vaccinations.57,63,65 Studies suggest that influenza infection has a stronger association with Guillain-Barré syndrome than does the vaccine, so vaccination may actually decrease the overall incidence.57,63

Varicella and Zoster Vaccines

Jump to section +

Before routine vaccination, wild-type varicella caused approximately 10,000 hospitalizations and 100 deaths annually.66 All 50 states mandate vaccination of school-aged children with the varicella vaccine.67 Adverse effects are generally mild and include erythema and pain at the injection site (Table 314,66,68–76). Local reactions occur in 19% of vaccinated children and 24% of vaccinated adolescents and adults (slightly more after the second dose).66 Both the varicella and the zoster vaccines contain the same attenuated Oka varicella strain. A recent Institute of Medicine report supports a causal relationship between varicella vaccination and disseminated Oka strain varicella-zoster infections such as pneumonia, meningitis, or hepatitis, especially in persons with demonstrated immunodeficiencies.27 Adverse events such as anaphylaxis may be related to sensitivity to vaccine components (e.g., gelatin) rather than to the attenuated vaccine virus itself. Nearly one in three unvaccinated persons in the United States will develop herpes zoster, and this risk increases with age.77 In general, zoster vaccine is well tolerated. The most common adverse effects are erythema (36%), pain or tenderness (35%), swelling (26%), and itchiness (7%) at the injection site.76 The benefits of vaccination and rates of adverse events are greater in persons 60 to 69 years of age compared with older adults.77

 Enlarge     Print

Table 3.

Statistics on Varicella and the Varicella Vaccine

Disease factorVaricellaVaricella vaccine

Average annual U.S. cases

4 million cases per year from 1980 to 199014,66

Prevents an estimated 3.5 million cases per year 68

Transmission route

Direct contact or airborne spread of respiratory secretions; transplacental

—

Transmission rate to susceptible contacts

90% in susceptible household contacts14,69 10% to 35% of persons with limited exposure14

Varicella zoster virus was transmitted from vaccine recipients with postvaccination rash to 3 household contacts from 1995 to 200570

Mortality

Prevaccine era: 105 deaths per year from 1970 to 199469

2 deaths ever reported from Oka strain of varicella zoster virus in immunocompromised or likely immunocompromised individuals72

Postvaccine era: 17 deaths per year from 2008 to 201171

Localized rash incidence

—

3% of children have a varicella-like rash at injection site 66

Generalized varicella-like rash incidence

100% of persons with varicella14

37 reports of rash from 1995 to 2005, some in immunocompromised patients70

Fever incidence

Most children

11.4 per 100,000 vaccinations73

Adverse event risk

—

20.8 per 100,000 vaccinations (2005)73

Anaphylaxis risk

—

76 cases ever reported14

Herpes zoster risk (in children younger than 18 years)

230 cases per 100,000 varicella cases in 200874

48 cases per 100,000 vaccinations (2008)74

Cerebellar ataxia risk

1 case per 4,000 varicella cases in children younger than 15 years14

Weak evidence 14

Encephalitis risk

1.8 cases per 10,000 varicella cases66

12 cases from 1995 to 200570

Pneumonia risk

1 case per 400 varicella cases in adults 75

5 cases ever reported (4 in immunocompromised children)14

Congenital varicella syndrome risk

< 2% risk from primary maternal varicella infection66 2% of infants 13 to 20 weeks of gestational age who have varicella14

0 cases in 87 women vaccinated before or during pregnancy 76

Information from references 14, 66, and 68 through 76.

Table 3.

Statistics on Varicella and the Varicella Vaccine

Disease factorVaricellaVaricella vaccine

Average annual U.S. cases

4 million cases per year from 1980 to 199014,66

Prevents an estimated 3.5 million cases per year 68

Transmission route

Direct contact or airborne spread of respiratory secretions; transplacental

—

Transmission rate to susceptible contacts

90% in susceptible household contacts14,69 10% to 35% of persons with limited exposure14

Varicella zoster virus was transmitted from vaccine recipients with postvaccination rash to 3 household contacts from 1995 to 200570

Mortality

Prevaccine era: 105 deaths per year from 1970 to 199469

2 deaths ever reported from Oka strain of varicella zoster virus in immunocompromised or likely immunocompromised individuals72

Postvaccine era: 17 deaths per year from 2008 to 201171

Localized rash incidence

—

3% of children have a varicella-like rash at injection site 66

Generalized varicella-like rash incidence

100% of persons with varicella14

37 reports of rash from 1995 to 2005, some in immunocompromised patients70

Fever incidence

Most children

11.4 per 100,000 vaccinations73

Adverse event risk

—

20.8 per 100,000 vaccinations (2005)73

Anaphylaxis risk

—

76 cases ever reported14

Herpes zoster risk (in children younger than 18 years)

230 cases per 100,000 varicella cases in 200874

48 cases per 100,000 vaccinations (2008)74

Cerebellar ataxia risk

1 case per 4,000 varicella cases in children younger than 15 years14

Weak evidence 14

Encephalitis risk

1.8 cases per 10,000 varicella cases66

12 cases from 1995 to 200570

Pneumonia risk

1 case per 400 varicella cases in adults 75

5 cases ever reported (4 in immunocompromised children)14

Congenital varicella syndrome risk

< 2% risk from primary maternal varicella infection66 2% of infants 13 to 20 weeks of gestational age who have varicella14

0 cases in 87 women vaccinated before or during pregnancy 76

Information from references 14, 66, and 68 through 76.

Vaccine Refusal

Jump to section +

The rate of parental refusal of all or selective immunizations is increasing.78 The American Academy of Family Physicians (AAFP) does not support immunization exemption policies except in cases of allergic or medical contraindication.79  Physicians should provide vaccine information statements to parents who are considering vaccine refusal or delay and direct them to credible sources of information (Table 4).80,81 If parents decide against a recommended vaccine, they should sign a refusal to vaccinate form, and this declination should be documented with provision of the vaccine information statement.82 The American Academy of Pediatrics (AAP) has developed a form that can be used to document vaccine refusal (http://www.aap.org/en-us/Documents/immunization_refusaltovaccinate.pdf). The CDC recommends against dismissing the patient or family from the practice if they refuse vaccination.83 However, the AAP now accepts this practice if done in a conscientious way.84,85

 Enlarge     Print

Table 4.

Credible Immunization Resources for Parents

American Academy of Pediatrics

https://www.healthychildren.org/english/safety-prevention/immunizations/pages/default.aspx

Centers for Disease Control and Prevention

http://www.cdc.gov/vaccines/vac-gen/default.htm

Children's Hospital of Philadelphia

http://www.chop.edu/centers-programs/parents-pack#.VsIAQLQrJmo

Every Child by Two Initiative, Vaccinate Your Family Program

http://www.vaccinateyourfamily.org

Immunization Action Coalition

http://www.vaccineinformation.org

Information from references 80 and 81.

Table 4.

Credible Immunization Resources for Parents

American Academy of Pediatrics

https://www.healthychildren.org/english/safety-prevention/immunizations/pages/default.aspx

Centers for Disease Control and Prevention

http://www.cdc.gov/vaccines/vac-gen/default.htm

Children's Hospital of Philadelphia

http://www.chop.edu/centers-programs/parents-pack#.VsIAQLQrJmo

Every Child by Two Initiative, Vaccinate Your Family Program

http://www.vaccinateyourfamily.org

Immunization Action Coalition

http://www.vaccineinformation.org

Information from references 80 and 81.

The AAFP has collaborated with the CDC and the AAP to develop a handout for parents who choose not to vaccinate (http://www.cdc.gov/vaccines/hcp/conversations/downloads/not-vacc-risks-color-office.pdf). Physicians should continue to discuss the benefits of immunizations at subsequent visits because some parents may reconsider the decision not to vaccinate, and some simply postpone certain vaccinations.

Consequences of Failure to Vaccinate

Jump to section +

In 2014, there were 667 cases of measles in the United States, mainly within an unvaccinated Amish community.20 In 2012, the largest U.S. pertussis outbreak since 1955 occurred, including 48,277 cases and 20 pertussis-related deaths.86 Pertussis cases have been linked to multiple causes, including waning immunity to the vaccine and children who are unvaccinated under non-medical exemption.87–89 The choice of some parents not to immunize increases the infection risk for all children, including those who are immunized. Sustained community-level transmission can occur in the presence of imperfect vaccine effectiveness and waning immunity, putting those who are susceptible—especially young infants and persons with medical contraindications—at increased risk.87 In the absence of a direct threat from disease, it is clear that some patients and parents will not participate in vaccination programs unless absolute safety can be assured. Full vaccination of students enhances the safety of all, but states vary in regard to acceptable reasons for parental vaccination refusal (Figure 1).90

 Enlarge     Print

Figure 1.

School vaccine exemption laws.

Reprinted with permission from Johns Hopkins Bloomberg School of Public Health. School exemption laws by state. http://www.vaccinesafety.edu/cc-exem.htm. Accessed January 24, 2017.

Figure 1.

School vaccine exemption laws.

Reprinted with permission from Johns Hopkins Bloomberg School of Public Health. School exemption laws by state. http://www.vaccinesafety.edu/cc-exem.htm. Accessed January 24, 2017.

Vaccine Adverse Event Reporting System

Jump to section +

The FDA and the CDC maintain the Vaccine Adverse Event Reporting System (VAERS) as a postmarketing safety surveillance program for adverse events that occur after immunization. Vaccine manufacturers and health care professionals are required to submit potential adverse events.91 VAERS receives approximately 30,000 reports each year. The effectiveness of VAERS as an early warning system was demonstrated by reports of an increased incidence of intussusception after immunization with rotavirus vaccine.91 In 1990, the Vaccine Safety Datalink, a collaboration between the CDC and nine health care organizations, was developed to investigate rare and serious adverse effects reported in the medical literature and to VAERS. The program monitors vaccine safety when a new vaccine is approved or when there are new vaccine recommendations.92

National Vaccine Injury Compensation Program

Jump to section +

The National Childhood Vaccine Injury Act of 1986 established the no-fault National Vaccine Injury Compensation Program to compensate patients and families injured by recommended vaccines. This law requires physicians who administer vaccines to document the provision of current vaccine information statements along with the vaccine manufacturer and lot number. The program's website includes a table of covered vaccine injuries.93 Injuries outside those listed and suspected to be vaccine related can also be compensated but require additional evidence. The program is funded by an excise tax on vaccines.

This article updates a previous article on this topic by Kimmel.94

Data Sources: Essential Evidence Plus was searched using the key word vaccine. PubMed was also searched using the key words vaccine adverse effects and thimerosal. Searches were also performed for individual vaccines, and the websites of the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Family Physicians, the Vaccine Adverse Event Reporting System, and the Health Resources and Services Administration were also searched. Search dates: October 28, 2015, to January 17, 2017.

The authors thank Kaitlyn Thomas for assistance with the preparation of the manuscript.

The Authors

show all author info

JEANNE P. SPENCER, MD, is program director at Conemaugh Family Medicine Residency Program, Johnstown, Pa., and a clinical assistant professor of family and community medicine at Drexel University College of Medicine, Philadelphia, Pa....

RUTH H. TRONDSEN PAWLOWSKI, MD, is an assistant program director at Conemaugh Family Medicine Residency Program.

STEPHANIE THOMAS, PharmD, is an associate director of the pharmacy residency program at Conemaugh Family Medicine Residency Program.

Address correspondence to Jeanne P. Spencer, MD, Conemaugh Family Medicine Residency Program, 1086 Franklin St., Johnstown, PA 15905 (e-mail: jspence@conemaugh.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

REFERENCES

show all references

1. Glanz JM, Wagner NM, Narwaney KJ, et al. A mixed methods study of parental vaccine decision making and parent-provider trust. Acad Pediatr. 2013;13(5):481–488....

2. Centers for Disease Control and Prevention. Possible side-effects from vaccines. http://www.cdc.gov/vaccines/vac-gen/side-effects.htm. Accessed December 9, 2015.

3. Beirne PV, Hennessy S, Cadogan SL, Shiely F, Fitzgerald T, MacLeod F. Needle size for vaccination procedures in children and adolescents. Cochrane Database Syst Rev. 2015;(6):CD010720.

4. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302(7):750–757.

5. Centers for Disease Control and Prevention. Fainting (syncope). http://cdc.gov/vaccinesafety/concerns/fainting.html. Accessed December 21, 2015.

6. Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374(9698):1339–1350.

7. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2011;60(29):993]. MMWR Recomm Rep. 2011;60(2):1–64.

8. Centers for Disease Control and Prevention. Vaccine excipient and media summary. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/excipient-table-2.pdf. Accessed February 1, 2016.

9. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases: general recommendations on immunization. http://www.cdc.gov/vaccines/pubs/pinkbook/genrec.html. Accessed February 24, 2016.

10. Immunization Action Coalition. Influenza vaccination of people with a history of egg allergy. http://www.immunize.org/catg.d/p3094.pdf. Accessed February 24, 2016.

11. Centers for Disease Control and Prevention. Latex in vaccine packaging. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/latex-table.pdf. Accessed May 18, 2016.

12. Kelso JM, Greenhawt MJ, Li JT, et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol. 2012;130(1):25–43.

13. Centers for Disease Control and Prevention. Vaccine information statement. Diphtheria, tetanus, and pertussis (DTaP) vaccine: what you need to know. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/dtap.pdf. Accessed February 23, 2016.

14. Stratton KR. et al, eds; Institute of MedicineAdverse Effects of Vaccines: Evidence and Causality. Washington, DC: National Academies Press; 2012.

15. Klein NP, Lewis E, Fireman B, et al. Safety of measles-containing vaccines in 1-year-old children. Pediatrics. 2015;135(2):e321–e329.

16. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases: rubella. http://www.cdc.gov/vaccines/pubs/pinkbook/rubella.html. Accessed May 16, 2016.

17. Feibelkorn AP, Goodson JL; Centers for Disease Control and Prevention. Chapter 3: infectious diseases related to travel. Measles (rubeola). https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/measles-rubeola. Accessed May 16, 2016.

18. M-M-R II. (measles, mumps, and rubella virus vaccine live) [package insert]. https://www.merck.com/product/usa/pi_circulars/m/mmr_ii/mmr_ii_pi.pdf. Accessed May 16, 2016.

19. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases: measles. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/meas.pdf. Accessed May 16, 2016.

20. Centers for Disease Control and Prevention. Measles, mumps and rubella (MMR) vaccine safety. http://www.cdc.gov/vaccinesafety/vaccines/mmr-vaccine.html. Accessed May 16, 2016.

21. National Vaccine Information Center. Can measles vaccine cause injury and death? http://www.nvic.org/vaccines-and-diseases/measles/measles-vaccine-injury-death.aspx. Accessed May 16, 2016.

22. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases: mumps. http://www.cdc.gov/vaccines/pubs/pinkbook/mumps.html. Accessed May 16, 2016.

23. Bohlke K, Davis RL, Marcy SM, et al.; Vaccine Safety Datalink Team. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics. 2003;112(4):815–820.

24. Centers for Disease Control and Prevention. Vaccine safety: VSD MMRV safety study. http://www.cdc.gov/vaccinesafety/vaccines/mmrv/vsd-mmrv-safety-study.html. Accessed February 23, 2016.

25. Centers for Disease Control and Prevention. Vaccine information statement. Meningococcal ACWY vaccines–MenACWY and MPSV4: what you need to know. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/mening.pdf. Accessed February 23, 2016.

26. Centers for Disease Control and Prevention. Vaccine information statement. Rotavirus vaccine: what you need to know. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/rotavirus.pdf. Accessed February 23, 2016.

27. Institute of Medicine. The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies. Washington, DC: National Academies Press; 2013.

28. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. Recommended immunization schedules for persons aged 0 through 18 years, United States, 2016. http://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf. Accessed May 17, 2016.

29. Grohskopf L; Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. Proposed recommendations 2016–17 influenza season. http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2016-02/flu-04-grohskopf.pdf. Accessed May 17, 2016.

30. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics. 2001;107(5):1147–1154.

31. Thompson WW, Price C, Goodson B, et al.; Vaccine Safety Datalink Team. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med. 2007;357(13):1281–1292.

32. Price CS, Thompson WW, Goodson B, et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics. 2010;126(4):656–664.

33. U.S. Food and Drug Administration. Vaccines, blood and biologics: thimerosal in vaccines. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228. Accessed February 24, 2016.

34. Mitkus RJ, King DB, Walderhaug MO, Forshee RA. A comparative pharmacokinetic estimate of mercury in U.S. infants following yearly exposures to inactivated influenza vaccines containing thimerosal. Risk Anal. 2014;34(4):735–750.

35. Godlee F, Smith J, Marcovitch H. Wakefield's article linking MMR vaccine and autism was fraudulent. BMJ. 2011;342d1678.

36. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet. 1999;353(9169):2026–2029.

37. Rowhani-Rahbar A, Fireman B, Lewis E, et al. Effect of age on the risk of fever and seizures following immunization with measles-containing vaccines in children. JAMA Pediatr. 2013;167(12):1111–1117.

38. Marin M, Broder KR, Temte JL, Snider DE, Seward JF; Centers for Disease Control and Prevention (CDC). Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-3):1–12.

39. Maldonado Y. Measles In: Behrman RE, Kliegman RM, Jenson HB, eds Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: Saunders; 2000: 946–951.

40. Maldonado Y. Mumps In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics 16th ed. Philadelphia, Pa: Saunders; 2000: 954–955.

41. Maldonado Y. Rubella In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics 16th ed. Philadelphia, Pa: Saunders; 2000: 951–954.

42. Centers for Disease Control and Prevention. Measles cases and outbreaks. http://www.cdc.gov/measles/cases-outbreaks.html. Accessed February 24, 2016.

43. Centers for Disease Control and Prevention. Mumps cases and outbreaks. http://www.cdc.gov/mumps/outbreaks.html. Accessed May 16, 2016.

44. Centers for Disease Control and Prevention. Notice to readers: final 2013 reports of nationally notifiable infectious diseases. MMWR Morb Mortal Wkly Rep. 2014;63(32):702.

45. Centers for Disease Control and Prevention. Manual for the surveillance of vaccine-preventable diseases: chapter 15: congenital rubella syndrome. http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html. Accessed May 16, 2016.

46. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-04):1–34.

47. Centers for Disease Control and Prevention. Transmission of measles. http://www.cdc.gov/measles/about/transmission.html. Accessed May 17, 2016.

48. Minnesota Department of Health. Rubella clinical information. http://www.health.state.mn.us/divs/idepc/diseases/rubella/hcp/clinical.html. Accessed May 17, 2016.

49. Patja A, Davidkin I, Kurki T, Kallio MJ, Valle M, Peltola H. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatr Infect Dis J. 2000;19(12):1127–1134.

50. Centers for Disease Control and Prevention. Measles (rubeola): complications of measles. http://www.cdc.gov/measles/about/complications.html. Accessed May 17, 2016.

51. Centers for Disease Control and Prevention. Mumps: for healthcare providers. http://www.cdc.gov/mumps/hcp.html. Accessed June 22, 2016.

52. Zimet GD, Rosberger Z, Fisher WA, Perez S, Stupiansky NW. Beliefs, behaviors and HPV vaccine: correcting the myths and the misinformation. Prev Med. 2013;57(5):414–418.

53. Stokley S, Jeyarajah J, Yankey D, et al.; Immunization Services Division, National Center for Immunization and Respiratory Diseases; Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination coverage among adolescents, 2007–2013, and postlicensure vaccine safety monitoring, 2006–2014—United States. MMWR Morb Mortal Wkly Rep. 2014;63(29):620–624.

54. Mapes D. It's not about sex, it's about cancer. http://www.fredhutch.org/en/news/center-news/2015/02/HPV-vaccine-not-increase-promiscuity.html. Accessed May 29, 2016.

55. Muncie HL Jr, LaBato AL. HPV vaccination: overcoming parental and physician impediments. Am Fam Physician. 2015;92(6):449–454.

56. Giacomet V, Penagini F, Trabattoni D, et al. Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults. Vaccine. 2014;32(43):5657–5661.

57. Miller ER, Moro PL, Cano M, Shimabukuro TT. Deaths following vaccination: what does the evidence show? Vaccine. 2015;33(29):3288–3292.

58. Haber P, Patel M, Pan Y, et al. Intussusception after rotavirus vaccines reported to US VAERS, 2006–2012. Pediatrics. 2013;131(6):1042–1049.

59. Cortese MM, Parashar UD; Centers for Disease Control and Prevention (CDC). Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2009;58(RR-2):1–25.

60. Cohn AC, MacNeil JR, Clark TA, et al.; Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-2):1–28.

61. Leca M, Bornet C, Montana M, Curti C, Vanelle P. Meningococcal vaccines: current state and future outlook. Pathol Biol (Paris). 2015;63(3):144–151.

62. Centers for Disease Control and Prevention. Vaccine information statements (VISs): serogroup B meningococcal (MenB) VIS. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/mening-serogroup.html. Accessed June 23, 2016.

63. Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis. 2013;13(9):769–776.

64. Dieleman J, Romio S, Johansen K, Weibel D, Bonhoeffer J, Sturkenboom M; VAESCO-GBS Case-Control Study Group. Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe. BMJ. 2011;343d3908.

65. Centers for Disease Control and Prevention (CDC). Preliminary results: surveillance for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine—United States, 2009–2010. MMWR Morb Mortal Wkly Rep. 2010;59(21):657–661.

66. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases: varicella. http://www.cdc.gov/vaccines/pubs/pinkbook/varicella.html. Accessed June 20, 2016.

67. Immunization Action Coalition. Varicella mandates for school and child care. http://www.immunize.org/laws/varicella.asp. Accessed December 9, 2015.

68. Centers for Disease Control and Prevention. Chickenpox (varicella): monitoring the impact of varicella vaccination. http://www.cdc.gov/chickenpox/surveillance/monitoring-varicella.html. Accessed May 13, 2016.

69. Marin M, Güris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella. recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1–40.

70. Galea SA, Sweet A, Beninger P, et al. The safety profile of varicella vaccine: a 10-year review. J Infect Dis. 2008;197(suppl 2):S165–S169.

71. Leung J, Bialek SR, Marin M. Trends in varicella mortality in the United States: data from vital statistics and the national surveillance system. Hum Vaccin Immmunother. 2015;11(3):662–668.

72. Leung J, Siegel S, Jones JF, et al. Fatal varicella due to the vaccine-strain varicella-zoster virus. Hum Vaccin Immunother. 2014;10(1):146–149.

73. Chaves SS, Haber P, Walton K, et al. Safety of varicella vaccine after licensure in the United States: experience from reports to the Vaccine Adverse Event Reporting System, 1995–2005. J Infect Dis. 2008;197(suppl 2):S170–S177.

74. Weinmann S, Chun C, Schmid DS, et al. Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005–2009. J Infect Dis. 2013;208(11):1859–1868.

75. Whitley RJ. Varicella-zoster virus In: Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases 5th ed. Philadelphia, Pa: Churchill Livingstone, 2000: 1580–1586.

76. Wise RP, Salive ME, Braun MM, et al. Postlicensure safety surveillance for varicella vaccine [published correction appears in JAMA. 2000; 284(24):3129]. JAMA. 2000;284(10):1271–1279.

77. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2012;(10):CD008858.

78. Flanagan-Klygis EA, Sharp L, Frader JE. Dismissing the family who refuses vaccines: a study of pediatrician attitudes. Arch Pediatr Adolesc Med. 2005;159(10):929–934.

79. American Academy of Family Physicians. Immunization exemptions. https://www.aafp.org/about/policies/all/immunizations-exemptions.html. Accessed June 20, 2016.

80. Immunization Action Coalition. Reliable sources of immunization information: where parents can go to find answers! http://www.immunize.org/catg.d/p4012.pdf. Accessed February 23, 2016.

81. Centers for Disease Control and Prevention. Provider resources for vaccine conversations with parents. http://www.cdc.gov/vaccines/hcp/conversations/conv-materials.html. Accessed February 23, 2016.

82. American Academy of Pediatrics. Documenting refusal to vaccinate. http://www.aap.org/en-us/Documents/immunization_refusaltovaccinate.pdf. Accessed February 25, 2016.

83. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2011;60:993]. MMWR Recomm Rep. 2011;60(2):1–64.

84. American Academy of Pediatrics. Reaffirmation: responding to parents who refuse immunization for their children. Pediatrics. 2013;131e1696.

85. Edwards KM, Hackell JM; Committee on Infectious Diseases, Committee on Practice and Ambulatory Medicine. Countering vaccine hesitancy. Pediatrics. Published online ahead of print August 25, 2016. http://pediatrics.aappublications.org/content/early/2016/08/25/peds.2016-2146. Accessed January 24, 2017.

86. Atwell JE, Salmon DA. Pertussis resurgence and vaccine uptake: implications for reducing vaccine hesitancy. Pediatrics. 2014;134(3):602–604.

87. Atwell JE, Van Otterloo J, Zipprich J, et al. Nonmedical vaccine exemptions and pertussis in California, 2010. Pediatrics. 2013;132(4):624–630.

88. Davis MM. Toward high-reliability vaccination efforts in the United States. JAMA. 2016;315(11):1115–1117.

89. California Legislative Information. Senate bill no. 277: public health: vaccinations (2015–2016). http://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=201520160SB277. Accessed June 7, 2016.

90. Johns Hopkins Bloomberg School of Public Health. School exemption laws by state. http://www.vaccinesafety.edu/cc-exem.htm. Accessed January 24, 2017.

91. Centers for Disease Control and Prevention. Vaccine safety: vaccine safety datalink (VSD). http://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html. Accessed January 11, 2016.

92. Health Resources and Services Administration. National vaccine injury compensation program. http://www.hrsa.gov/vaccinecompensation/vaccinetable.html. Accessed February 23, 2016.

93. Health Resources and Services Administration. Vaccine injury table. http://www.hrsa.gov/vaccinecompensation/vaccineinjurytable.pdf. Accessed February 25, 2016.

94. Kimmel SR. Vaccine adverse events: separating myth from reality. Am Fam Physician. 2002;66(11):2113–2121.

 

 

Copyright © 2017 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

  • PRINT

Want to use this article elsewhere? Get Permissions


More in AFP


Editor's Collections

Related Content

More in Pubmed


MOST RECENT ISSUE


Mar 1, 2021

Access the latest issue of American Family Physician

Read the Issue


Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article